Mechanistic insights and therapeutic interventions of mitochondrial quality control in chemotherapy-related cognitive impairment

Highlights

• •MQC dysfunction is a central, unifying mechanism in chemotherapy-related cognitive impairment (CRCI).
• •Diverse chemotherapeutics disrupt all five MQC pillars: biogenesis, mitophagy, dynamics, proteostasis, and MDVs.
• •Agent-specific MQC vulnerabilities drive neuroinflammation, BBB disruption, synaptic loss, and cognitive deficits.
• •Mitochondria-targeted interventions offer a robust framework for CRCI neuroprotection without anticancer efficacy compromise.

Abstract

Chemotherapy-related cognitive impairment (CRCI), colloquially termed “chemobrain,” remains a debilitating and underaddressed sequela of cancer treatment. Despite its prevalence and profound impact on quality of life, the precise pathophysiological mechanisms remain incompletely understood. This review synthesizes emerging evidence positioning mitochondrial quality control (MQC) dysfunction as a central mechanistic hub in CRCI pathogenesis. We critically evaluate how diverse chemotherapeutic agents, including anthracyclines, alkylating agents, platinum compounds, antimetabolites, and microtubule inhibitors, converge on distinct yet overlapping pathways of MQC impairment. These agent-specific mechanisms collectively compromise the five fundamental pillars of MQC: biogenesis, mitophagy, dynamics, and proteostasis, along with the formation of mitochondria-derived vesicles. MQC failure subsequently drives a feed-forward cycle of neuroinflammation, blood-brain barrier disruption, synaptic loss, and ultimately, cognitive dysfunction. We further examine promising therapeutic strategies targeting MQC, encompassing mitochondria-targeted antioxidants, metabolic regulators, biogenesis activators, mitochondrial dynamics modulators, mitophagy activators, multi-targeted drugs, as well as physical and nutritional interventions that collectively enhance neuronal mitochondrial resilience. By elucidating the mechanistic centrality of MQC in CRCI, this review provides a robust framework for developing targeted interventions that may preserve cognitive function without compromising anticancer efficacy, thereby addressing a critical unmet need in cancer survivorship care and accelerating the transition towards precision neuroprotection in oncology.

Abbreviations

6BIO

6-bromoindirubin-3′-oxime

AAA+

ATPases Associated with diverse cellular Activities

A1AR

adenosine receptor A1

AChE

acetylcholinesterase

ALCAR

Acetyl-l-Carnitine

AMPK

AMP-activated protein kinase

AP-2

Adaptin-2

APOE

apolipoprotein E

ATAD3A

autophagy and beclin 1 regulator 1

ATF4

activating transcription factor 4

ATF5

activating transcription factor 5

ATGs

autophagy-related genes

ATM

ataxia-telangiectasia mutated

ATP

adenosine triphosphate

BBB

blood-brain barrier

BDNF

brain-derived neurotrophic factor

BNIP3

Bcl-2/adenovirus E1B 19 kDa-interacting protein 3

BU

Busulfan

CaMK

calcium/calmodulin-dependent protein kinase

cAMP

cyclic AMP

CAT

catalase

CHCHD4

coiled-coil-helix-coiled-coil-helix domain containing 4

CK2

casein kinase 2

CL

Cardiolipin

CLPP

caseinolytic protease P

ClpXP

caseinolytic protease XP

CMF

Cyclophosphamide, Methotrexate, 5-Fluorouracil

CNS

Central Nervous System

CoQ10

Coenzyme Q10

COWAT

Controlled Oral Word Association Test

CRCI

Chemotherapy-related cognitive impairment

CREB

cAMP response element-binding protein

CTX

Cyclophosphamide

DAMPs

damage-associated molecular patterns

DHA

docosahexaenoic acid

DLK

dual leucine zipper kinase

ΔΨm

mitochondrial membrane potential

DNM2

Dynamin 2

DOX

Doxorubicin

DRF

diroximel fumarate

DRP1

dynamin-related protein 1

DTI

diffusion tensor imaging

DVE-1

defective in adult life 1

eIF2α

eukaryotic initiation factor 2 alpha

EPA

eicosapentaenoic acid

ER

endoplasmic reticulum

ERRα

estrogen-related receptor alpha

ETC

electron transport chain

EVs

Extracellular vesicles

FA

fractional anisotropy

5-FU

5-fluorouracil

FKBP8

FK506-binding protein 8

fMRI

functional MRI

FPRs

formyl peptide receptors

FUNDC1

FUN14 domain-containing protein 1

FXDH

Fangxia-Dihuang Decoction

GA

Ganoderic acid

GSDMD

Gasdermin D

GFAP

glial fibrillary acidic protein

GPX4

glutathione peroxidase 4

GSH

glutathione

GSH-Px

glutathione peroxidase

HDAC

histone deacetylase

HIF-1α

hypoxia-inducible factor 1 alpha

HR1/HR2

heptad repeat regions 1 and 2

HSP10

heat shock protein 10

HSP60

heat shock protein 60

HSP70

heat shock protein 70

HSPA9

heat shock protein A9

HSPD1

heat shock protein D1

HtrA2/Omi

high-temperature requirement A2/Omi

HVLT-R

Hopkins Verbal Learning Test-Revised

ICDH

isocitrate dehydrogenase

i-AAA

inner membrane-associated AAA protease

IL-1β

interleukin-1 beta

IL-6

interleukin-6

IMM

inner mitochondrial membrane

IMS

intermembrane space

INF2

inverted formin 2

ISR

integrated stress response

JMJD-1.2/Phf8

Jumonji domain-containing protein 1.2/PHD finger protein 8

JMJD-3.1/Jmjd3

Jumonji domain-containing protein 3.1

KIF5

kinesin family member 5

KXS

Kai-Xin-San

L-Dopa

l-Dopa

LIR

LC3-interacting region

LonP1

Lon protease 1

L-OPA1

long OPA1

LTP

long-term potentiation

m-AAA

matrix-associated AAA protease

MB

Mitochondrial biogenesis

MDA

malondialdehyde

MDH

malate dehydrogenase

Mdivi-1

mitochondrial fission inhibitor 1

MDVs

Mitochondria-derived vesicles

MERCs

ER-mitochondria contact sites

MESNA

2-Mercaptoethane Sulfonate Sodium

MFF

mitochondrial fission factor

MFN1/2

mitofusins 1 and 2

MICOS

mitochondrial contact site and cristae organizing system

MiD49/51

mitochondrial dynamics proteins of 49 and 51

Miro1/2

Mitochondrial Rho GTPases 1 and 2

MMPs

matrix metalloproteinases

MMP-2/9

matrix metalloproteinases-2/9

MMF

monomethyl fumarate

MOMP

mitochondrial outer membrane permeabilization

MQC

mitochondrial quality control

mPTP

mitochondrial permeability transition pore

MRC

maximal respiratory capacity

MRI

magnetic resonance imaging

MRS

magnetic resonance spectroscopy

mtDNA

mitochondrial DNA

mtUPR

mitochondrial unfolded protein response

MTS

mitochondrial targeting sequences

mTOR

mammalian target of rapamycin

mTORC1

mammalian target of rapamycin complex 1

mTORC2

mammalian target of rapamycin complex 2

MUL1

mitochondrial ubiquitin ligase 1

NAC

N-acetylcysteine

NAD⁺

nicotinamide adenine dinucleotide

NADH

nicotinamide adenine dinucleotide

NAMPT

nicotinamide phosphoribosyltransferase

NDP52

nuclear dot protein 52 kDa

NEMGs

nuclear-encoded mitochondrial genes

NF-κB

nuclear factor kappa B

NIX

BNIP3L

NLS

nuclear localization sequences

NLRP3

NLR family pyrin domain containing 3

NMN

Nicotinamide mononucleotide

NRF1/2

nuclear respiratory factors 1 and 2

OCR

oxygen consumption rate

OIE

Oroxylum Indicum Extract

OMM

outer mitochondrial membrane

OPA1

optic atrophy protein 1

OPTN

optineurin

ox-CL

oxidized CL

OXPHOS

oxidative phosphorylation

PAESe

Phenyl-2-aminoethyl Selenide

Parkin

E3 ubiquitin ligase Parkin

PARL

presenilin-associated rhomboid-like protein

p38 MAPK

p38 mitogen-activated protein kinase

PGC-1α

peroxisome proliferator-activated receptor gamma coactivator-1 alpha

PERK

PKR-like endoplasmic reticulum kinase

PFKFB3

6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3

PGAM5

phosphoglycerate mutase 5

PHB2

Prohibitin 2

PINK1

PTEN-induced putative kinase 1

PKA

protein kinase A

PPARα

peroxisome proliferator-activated receptor alpha

PRC

PGC-1 related coactivator

PSD-95

postsynaptic density protein 95

RNS

reactive nitrogen species

RNF185

ring finger protein 185

ROS

reactive oxygen species

SARM1

sterile alpha and TIR motif containing 1

SDH

succinate dehydrogenase

SIRT1

Sirtuin 1

SIRT3

Sirtuin 3

sMRI

structural MRI

SNX9

sorting nexin 9

SOD2

superoxide dismutase 2

S-OPA1

short OPA1

SRC

spare respiratory capacity

TBK1

TANK-binding kinase 1

TCA

tricarboxylic acid

TCM

traditional Chinese medicine

TFAM

mitochondrial transcription factor A

TFB1M

mitochondrial transcription factor B1

TFB2M

mitochondrial transcription factor B2

TFEB

Transcription Factor EB

TLRs

toll-like receptors

TMT

Trail Making Test

TMZ

Temozolomide

TNF-α

Tumor necrosis factor-alpha

TNTs

Tunneling nanotubes

TWEAK

tumor necrosis factor-related protein 3

UBA

ubiquitin-associated

Ub-dependent

ubiquitin-dependent

Ub-independent

ubiquitin-independent

Ubl

ubiquitin-like

UBL-5

ubiquitin-like 5

ULK1

Unc-51 like autophagy activating kinase 1

UPRE

unfolded protein response element

UPS

Ubiquitin-Proteasome System

VBM

Voxel-based morphometry

VCR

Vincristine

VDAC1

voltage-dependent anion channel 1

ZO-1

Zona Occludens-1

α-KGDH

alpha-ketoglutarate dehydrogenase.

Introduction

Chemotherapy, a cornerstone of cancer treatment, often induces a debilitating constellation of cognitive impairments collectively termed chemotherapy-related cognitive impairment (CRCI) (colloquially termed “chemobrain”), significantly impacting patients’ quality of life even long after treatment cessation. These impairments manifest as deficits in attention, memory, processing speed, and executive function, hindering patients’ ability to return to work, maintain social connections, and perform daily activities. While the precise mechanisms underlying CRCI remain incompletely understood, accumulating evidence points towards a complex interplay of neurotoxic effects, including neuroinflammation, blood-brain barrier (BBB) disruption, and neuronal dysfunction [1]. Chemotherapy can trigger neuroinflammatory responses, characterized by glial activation and the release of pro-inflammatory cytokines, potentially disrupting neuronal signaling and contributing to cognitive decline [2]. Furthermore, chemotherapy can compromise BBB integrity through tight junction disruption, leading to increased permeability and potentially exposing the central nervous system to peripheral toxins or cytokines [3].

Mitochondria, the powerhouses of cells, play a critical role in neuronal function by regulating energy production, calcium homeostasis, cell fate, and neurotransmitter release. Their dysfunction is increasingly recognized as a central driver of various neurological disorders, including CRCI [4]. Chemotherapy can induce mitochondrial dysfunction through multiple mechanisms, including increased reactive oxygen species (ROS) production, mitochondrial DNA (mtDNA) damage, and impaired oxidative phosphorylation [5]. This mitochondrial damage can trigger neuronal apoptosis and synaptic loss, directly contributing to the cognitive decline observed in CRCI. Crucially, mitochondrial quality control (MQC), a dynamic network encompassing mitochondrial biogenesis, mitophagy (selective degradation of damaged mitochondria), fission/fusion dynamics (structural remodeling), and proteostasis (maintenance of protein integrity), is essential for maintaining mitochondrial health [6]. Dysregulation of MQC, leading to the accumulation of damaged mitochondria, has been implicated in the pathogenesis of various diseases, including neurodegenerative disorders and cancer [7]. Emerging evidence suggests that impaired MQC represents a key mechanism linking chemotherapy exposure to neurotoxicity and the subsequent development of CRCI.

This review critically examined the mechanistic underpinnings of CRCI, focusing on the pivotal role of mitochondrial dysfunction and impaired MQC. We dissected the interplay between chemotherapy-induced neuroinflammation, BBB disruption, and mitochondrial damage in driving cognitive impairment. Furthermore, we explored the therapeutic potential of targeting MQC pathways, including the regulation of PINK1/Parkin-mediated mitophagy, SIRT1/PGC-1α-driven mitochondrial biogenesis, and dynamin-related protein 1 (DRP1)/Mfn-mediated mitochondrial dynamics, to mitigate chemotherapy-induced neurotoxicity. Finally, we highlighted promising research avenues, such as personalized MQC-targeted interventions based on genetic profiles, and future directions for developing effective strategies to prevent and treat this debilitating condition. By synthesizing current knowledge of CRCI pathogenesis with a focus on MQC mechanisms, this review aims to inform translational research and accelerate the development of much-needed therapeutic interventions.

Clinical manifestations of CRCI

Epidemiology of CRCI

CRCI represents a significant clinical challenge affecting a substantial proportion of cancer survivors. Epidemiological studies indicate that 17-75% of patients receiving chemotherapy experience some degree of cognitive dysfunction during treatment, with 15-35% demonstrating persistent impairment months or even years after treatment cessation [8]. This wide prevalence range reflects heterogeneity in assessment methods (objective neuropsychological tests vs. subjective self-reports), cancer types, treatment regimens, and follow-up durations across different studies [9]. A recent meta-analysis standardized these variables, estimating a pooled prevalence of 41% during treatment and 24% at ≥6 months post-treatment, confirming CRCI as a clinically meaningful sequela [10].

Certain patient populations exhibit increased vulnerability to CRCI, with contributions from psychological (anxiety, depression), biological (comorbidities), and genetic determinants [9]. Advanced age represents a significant risk factor, with elderly patients showing greater susceptibility due to age-related declines in mitochondrial reserve and cognitive reserve [11,12]. Pre-existing cognitive impairment, lower educational attainment (a proxy for cognitive reserve), and genetic polymorphisms such as apolipoprotein E (APOE) ε4 allele, a well-established risk factor for Alzheimer's disease, may predispose individuals to more severe or persistent CRCI [13]. Additionally, women appear more susceptible than men, particularly those undergoing treatment for breast cancer, where CRCI rates reach 75% during active treatment and 35% at long-term follow-up, potentially due to estrogen-mediated effects on mitochondrial function [14,15].

Treatment-related factors significantly influence CRCI risk. High-dose regimens, longer treatment durations, and combination therapies are associated with increased incidence and severity of cognitive impairment [16]. Specific agents demonstrate pronounced neurotoxicity: platinum compounds (cisplatin, oxaliplatin) induce mtDNA damage and ROS overproduction; taxanes (paclitaxel, docetaxel) disrupt mitochondrial dynamics; anthracyclines (doxorubicin) trigger lipid peroxidation; while methotrexate and 5-fluorouracil impair nucleotide metabolism critical for mitochondrial biogenesis [17,18]. Notably, the temporal pattern of CRCI varies considerably: some patients experience transient symptoms resolving post-treatment, while others develop delayed-onset impairment or persistent deficits lasting years or even decades, possibly reflecting differential individual MQC capacity [19]. For example, cognitive complaints (attention and concentration) significantly increased in tamoxifen users but not in women on exemestane, likely due to tamoxifen’s estrogen agonist activity disrupting mitochondrial respiration in hippocampal neurons [20].

Cancer type influences CRCI prevalence, with breast cancer survivors being the most extensively studied population. However, significant cognitive effects have been documented across multiple malignancies including solid cancers (colorectal, ovarian, testicular) and hematological cancers [21]. Recent longitudinal studies reveal that approximately 30% of cancer survivors continue experiencing cognitive difficulties 5-10 years post-treatment, significantly impacting survivorship quality and functional independence [19,22]. These long-term effects strongly suggest that chemotherapy induces lasting perturbations in MQC pathways, as the accumulation of fomitochondrial damage is a hallmark of chronic neurological dysfunction.

Clinical features of CRCI

Neuropsychological manifestations of CRCI

CRCI encompasses a diverse spectrum of neurocognitive deficits across multiple domains, with a characteristic pattern of vulnerability that distinguishes it from age-related cognitive decline. Working memory and executive function appear particularly susceptible, as patients demonstrate impaired ability to maintain and manipulate information simultaneously, reduced cognitive flexibility, and difficulties with planning and problem-solving [23,24]. Processing speed shows consistent deficits across studies, manifesting as slowed reaction times and increased mental fatigue during sustained cognitive tasks [25,26]. Attention deficits, particularly in sustained and divided attention, further compromise cognitive performance, with patients struggling to filter irrelevant stimuli during complex tasks [25,27]. Learning and retrieval of new information are frequently affected, while remote memories typically remain intact, suggesting a selective impact on hippocampal-dependent memory encoding [28].

Neuropsychological assessment remains the gold standard for CRCI diagnosis, employing comprehensive test batteries tailored to detect domain-specific deficits: the Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT), and Controlled Oral Word Association Test (COWAT) are commonly used [29]. However, a concerning “assessment gap” persists between subjective cognitive complaints (e.g., difficulty managing medications or multitasking) and objective test performance, with patients often reporting more severe impairment than those detected through formal testing [30]. This discrepancy highlights the limitations of traditional neuropsychological measures, which often lack ecological validity, fail to capture real-world cognitive challenges, and underscore the need for novel assessment tools, such as ecological momentary assessment or digital cognitive phenotyping, to bridge this divide.

The impact of gender and age on CRCI

Gender and age significantly influence the incidence and severity of CRCI. Epidemiological studies have demonstrated that male patients are often at a higher risk for neurological complications compared to their female counterparts, potentially due to biological differences in drug metabolism and neuroprotection capacity [31]. Additionally, the intersection of age with gender further complicates this dynamic; older males may experience more pronounced cognitive decline than older females, highlighting the need for gender-sensitive approaches in treatment [32]. Age-related factors, such as neuroplasticity and the brain's ability to recover from injury, also play a role, with younger patients generally exhibiting better resilience to the cognitive effects of chemotherapy [33]. Thus, clinicians must consider both gender and age when assessing the risk of brain damage in patients undergoing chemotherapy, tailoring interventions to mitigate these risks effectively.

Neuroimaging insights into the neural substrates of CRCI

Advanced neuroimaging techniques have provided critical insights into the structural and functional neural substrates of CRCI, revealing chemotherapy-induced alterations that parallel cognitive domain impairments. Multimodal magnetic resonance imaging (MRI) approaches, including structural MRI (sMRI), diffusion tensor imaging (DTI), and functional MRI (fMRI), enable in vivo characterization of neural changes and their relationship to cognitive decline.

Structural MRI studies consistently demonstrate gray matter volume reductions in frontotemporal regions, the cerebellum, and the hippocampus following chemotherapy [34]. These volumetric changes correlate directly with deficits in information processing speed (frontal lobe), memory encoding (hippocampus), and executive function (prefrontal cortex). Voxel-based morphometry (VBM) analyses have documented 5-8% gray matter atrophy in frontotemporal regions that persists for months to years post-treatment, with atrophy magnitude strongly predicting performance on the TMT and HVLT-R [35]. Notably, hippocampal volume loss, observed even in patients with subtle cognitive complaints, aligns with preclinical evidence linking chemotherapy-induced mitochondrial dysfunction to hippocampal neurogenesis impairment, providing a potential mechanistic link between structural changes and memory deficits.

Diffusion tensor imaging (DTI) reveals microstructural white matter damage, with reduced fractional anisotropy (FA) in the posterior cingulate gyrus, corpus callosum, and frontal lobe tracts [36]. The posterior cingulate appears particularly vulnerable due to its high metabolic demand and dense mitochondrial population, making it sensitive to oxidative stress induced by chemotherapy [36]. Reduced FA, indicative of axonal damage or demyelination, correlates with self-reported cognitive difficulties and objective deficits in attention and processing speed [37]. However, some studies have failed to consistently detect white matter changes, likely due to heterogeneity in chemotherapy regimens (e.g., platinum-based vs. taxane-based) and baseline patient characteristics [38].

Functional MRI studies highlight aberrant neural network dynamics in CRCI. During spatial memory tasks, chemotherapy survivors exhibit heightened hippocampal-precuneus connectivity that correlates with poorer subjective cognitive function, suggesting a maladaptive attempt to compensate for neural inefficiency [36]. N-back task performance reveals blunted parietal-frontal activation during moderate difficulty levels, alongside exaggerated frontal activation at maximum difficulty, patterns indicative of reduced neural reserve [39,40]. Resting-state fMRI further identifies hyperconnectivity in networks governing emotional processing, attentional control, and working memory (e.g., precuneus and executive control networks), coupled with reduced fusiform gyrus activation during task performance [41]. These functional alterations likely reflect compensatory mechanisms strained by mitochondrial energy deficits, as neurons struggle to maintain synaptic transmission under metabolic stress.

Chemotherapy-induced neurotoxicity

Neuroinflammation

Neuroinflammation represents a critical mechanism underlying chemotherapy-induced neurotoxicity and subsequent cognitive impairment, serving as a key link between systemic treatment exposure and CNS dysfunction. Chemotherapeutic agents initiate neuroinflammatory cascades through several converging pathways: peripheral inflammation triggered by chemotherapy can propagate to the CNS via circulating cytokines crossing the compromised BBB, activation of vagal afferents, and transport through circumventricular organs lacking typical BBB protection [42,43]. Additionally, direct CNS penetration of certain agents, particularly methotrexate, 5-fluorouracil (5-FU), and platinum compounds, can initiate local inflammatory responses independent of peripheral signals [44].

Glial cells serve as primary mediators of neuroinflammation in CRCI. Microglia, the resident immune cells of the CNS, undergo morphological and functional transformations following chemotherapy exposure, shifting from a ramified, surveillance phenotype to an activated, pro-inflammatory state characterized by enlarged cell bodies and shortened processes [45,46]. In vitro and animal studies demonstrate that doxorubicin directly activates microglial toll-like receptors (TLRs), particularly TLR-4, triggering nuclear factor kappa B (NF-κB) signaling and subsequent production of pro-inflammatory cytokines [47,48]. Astrocytes also similarly exhibit reactive phenotypes following chemotherapy exposure, with altered expression of glial fibrillary acidic protein (GFAP) and compromised glutamate homeostasis, contributing to neuronal excitotoxicity and oxidative stress through impaired uptake of extracellular glutamate [49,50].

The neuroinflammatory cytokine profile in CRCI has been extensively characterized. Tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) show consistent elevation in both preclinical models and cancer patients following chemotherapy [51,52]. These cytokines disrupt long-term potentiation (LTP) in the hippocampus by altering NMDA receptor trafficking, impair synaptic plasticity through dysregulation of BDNF signaling, and suppress adult neurogenesis in the subgranular zone, particularly in the hippocampus, providing a mechanistic link to memory and learning deficits [48,53].

The temporal dynamics of neuroinflammation correlate meaningfully with cognitive trajectories. Acute inflammatory responses typically peak 1-3 days post-chemotherapy administration, corresponding with immediate cognitive deficits [54]. However, evidence from both rodent models and human studies reveals persistent neuroinflammatory signatures, including sustained microglial activation and cytokine elevation, lasting months to years after treatment cessation, potentially explaining delayed-onset and chronic cognitive impairments [55]. Importantly, neuroinflammation directly impacts mitochondrial function, creating a pathological feedback loop perpetuating neurotoxicity: pro-inflammatory cytokines disrupt mitochondrial respiration by inhibiting complex I activity, increase ROS production through mitochondrial permeability transition pore (mPTP) opening, and compromise mitochondrial membrane potential [56]. Conversely, mitochondrial damage releases mtDNA and formyl peptides that act as damage-associated molecular patterns (DAMPs), further activating microglia via TLR-9 and formyl peptide receptors (FPRs) and exacerbating neuroinflammation [57]. This bidirectional relationship between neuroinflammation and mitochondrial dysfunction represents a promising therapeutic target for CRCI intervention strategies.

Blood-brain barrier disruption

The BBB constitutes a sophisticated neurovascular interface regulating molecular exchange between circulation and brain parenchyma. Comprised of specialized endothelial cells connected by tight junctions (claudins, occludins, ZO-1), basement membrane components, pericytes, and astrocytic endfeet, the BBB maintains CNS homeostasis through selective permeability to nutrients while excluding toxins and pathogens [58]. Emerging evidence indicates that chemotherapy-induced BBB disruption represents a pivotal mechanism in CRCI pathogenesis, facilitating neurotoxicity through both direct and indirect pathways.

Chemotherapeutic agents compromise BBB integrity through both structural and functional alterations. Tight junction proteins, particularly occludin and claudin-5, show significant downregulation following exposure to doxorubicin and methotrexate in preclinical models, with concomitant redistribution of ZO-1 from the cell membrane to the cytoplasm [59,60]. Endothelial oxidative stress, triggered by platinum compounds, disrupts junctional complexes through activation of matrix metalloproteinases (MMPs), particularly MMP-9, which degrade basement membrane components and tight junction proteins [61]. Additionally, chemotherapy-induced pericyte loss (observed after paclitaxel and cisplatin treatment) compromises BBB structural support and regulatory functions, further increasing permeability by impairing endothelial survival signals [62,63].

The consequences of BBB disruption extend beyond the simple passive diffusion of chemotherapeutic agents into the CNS. Barrier compromise permits CNS entry of peripheral inflammatory mediators, including cytokines, chemokines, and activated immune cells that further exacerbate neuroinflammation [64]. Notably, anthracyclines, despite limited CNS penetration, can directly compromise BBB integrity through systemic inflammatory responses (via TNF-α-mediated endothelial activation) and oxidative damage to endothelial mitochondria, creating a “secondary hit” that amplifies neurotoxicity [42,65].

Direct neuronal damage

Chemotherapeutic agents exert direct neurotoxic effects through multiple convergent mechanisms culminating in neuronal dysfunction and death, with particular vulnerability of hippocampal and prefrontal cortical neurons, brain regions critical for memory and executive function. DNA damage constitutes a critical mechanism: while targeting rapidly dividing cancer cells, chemotherapy also affects post-mitotic neurons, where DNA damage repair mechanisms are less efficient compared to those in dividing cells [66]. Cisplatin forms intrastrand and interstrand DNA adducts in neurons, disrupting transcription and inducing p53-dependent apoptosis through mitochondrial outer membrane permeabilization (MOMP) [67]. Topoisomerase inhibitors like etoposide create persistent DNA strand breaks in neurons, leading to sustained activation of ataxia-telangiectasia mutated (ATM) kinase and subsequent cell cycle re-entry, a lethal event for post-mitotic cells [68].

Certain chemotherapy profoundly impacts neuronal structural integrity and plasticity. Taxanes disrupt microtubule dynamics by stabilizing polymerized tubulin, impairing axonal transport of mitochondria and synaptic vesicles, critical for maintaining distal synapses in projection neurons [69]. Platinum compounds and vinca alkaloids reduce dendritic spine density and alter spine morphology in hippocampal CA1 and prefrontal cortical neurons, correlating with memory and executive function deficits [70,71]. High-resolution two-photon imaging reveals that even sublethal chemotherapy exposure significantly compromises neuronal connectivity through retraction of dendritic branches and synapse elimination, preceding overt cell death by weeks [70,72]. These structural alterations manifest functionally as impaired LTP at hippocampal Schaffer collateral-CA1 synapses and reduced synaptic transmission, driven by decreased AMPA receptor expression and trafficking [69].

Notably, direct neuronal damage is frequently amplified by mitochondrial dysfunction: cisplatin-induced mtDNA damage impairs respiratory chain function [73], while taxane-mediated microtubule disruption blocks mitochondrial transport to dendritic spines, creating localized mitochondrial energy deficits at synapses [74,75]. This convergence of nuclear and mitochondrial damage pathways helps explain why neurons, despite their post-mitotic status, remain highly vulnerable to chemotherapy-induced toxicity.

Mechanisms of Mitochondrial Quality Control

Mitochondrial Biogenesis

Concept and canonical process of mitochondrial Biogenesis

Mitochondrial biogenesis (MB), a critical component of MQC, governs the structural and functional integrity of the oxidative phosphorylation system, playing a pivotal role in cellular energy production [76]. Contrary to de novo mitochondrial synthesis, MB involves the integration of lipids, proteins, and mtDNA into pre-existing mitochondria, increasing their mass before division through fission to expand mitochondrial number [77,78]. This process encompasses several key steps (Fig. 1): i) synthesis of inner (IMM) and outer mitochondrial membranes (OMM); ii) synthesis of mitochondrially-encoded proteins; iii) synthesis and import of nuclear-encoded mitochondrial proteins; and iv) replication of mtDNA [79].

Fig. 1.

Molecular mechanisms of mitochondrial biogenesis (AMPK, AMP-activated protein kinase; CLPP, caseinolytic mitochondrial matrix peptidase proteolytic subunit; DRP1, dynamin-related protein 1; ER, endoplasmic reticulum; Fis1, fission 1; LC3, microtubule-associated protein 1 light chain 3; FUNDC1, FUN14 domain-containing protein 1; LONP1, lon peptidase 1, mitochondrial; MFN1/2, mitofusins 1/2; NIX/BNIP3, Bcl-2/adenovirus E1B 19 kDa-interacting protein 3/3 L; OPA1, optic atrophy; OPTN, optineurin; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1α; PHB2, prohibitin 2; SIRT1, sirtuin 1).

MB relies on the coordinated transcriptional control of both mitochondrial and nuclear-encoded mitochondrial genes (NEMGs). While the mitochondrial genome encodes only 13 respiratory chain subunits, NEMGs provide the vast majority of gene products required for MB, including structural components (e.g., membrane transporters) and biochemical machinery (e.g., OXPHOS complex assembly factors) [80]. The expression of NEMGs is regulated by a network of transcription factors, including nuclear respiratory factors 1 and 2 (NRF1/2), estrogen-related receptor alpha (ERRα), peroxisome proliferator-activated receptor alpha (PPARα), and c-Myc. These factors exert their influence by binding to NEMG promoters and interacting with co-activators, notably the peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family, including PGC-1α, PGC-1β, and PRC, thereby fine-tuning NEMG expression [81,82].

Molecular mechanisms of mitochondrial biogenesis

MB is a complex process regulated by interconnected signaling pathways, with the AMPK/PGC-1α axis serving as a central driver [83]. The following sections dissect the key molecular mechanisms underlying this pathway.

PGC-1α

Encoded by the PPARGC1A gene, PGC-1α functions as a master regulator of MB [84]. Upon activation via AMPK-mediated phosphorylation (at Ser570) or SIRT1-mediated deacetylation (at Lys772/795), PGC-1α translocates to the nucleus, where it orchestrates the PGC-1α/NRF-1/2/mitochondrial transcription factor A (TFAM) cascade. This cascade stimulates transcription, replication, and translation of mtDNA and associated proteins, ultimately increasing mitochondrial mass and maintaining cellular energy homeostasis [85,86]. NRF1/2, acting as positive transcriptional regulators, bind to the promoters of TFAM, mitochondrial transcription factor B1 (TFB1M), and TFB2M, further amplifying MB [87,88]. TFAM, positioned upstream of the transcriptional start site, recruits mitochondrial RNA polymerase to generate RNA primers. Subsequently, DNA polymerase gamma, assisted by the DNA helicase TWINKLE and mitochondrial single-stranded DNA-binding protein, replicates mtDNA, facilitating the formation of new mitochondria [89].

Recent studies reveal additional layers of PGC-1α-mediated regulation: PGC-1α interacts with ERRα to promote expression of the deacetylase Sirtuin 3 (SIRT3). SIRT3 then deacetylates and activates FOXO3a, which transcriptionally upregulates mtDNA-encoded electron transport chain (ETC) proteins and the antioxidant enzyme superoxide dismutase 2 (SOD2), thereby enhancing neuronal MB while mitigating ROS production. Notably, deacetylated FOXO3a also upregulates mitophagy mediators Parkin and Pink1, linking MB to mitochondrial degradation pathways and highlighting PGC-1α’s role in coordinating MQC processes [90].

AMPK

AMPK, a heterotrimeric complex composed of α (catalytic), β, and γ (regulatory) subunits, functions as a cellular energy sensor [91]. When ATP levels decline (e.g., during neuronal injury or increased energy demand), the rising AMP/ATP ratio allosterically activates AMPK, which then phosphorylates PGC-1α to stimulate MB via the PGC-1α/NRF1/2 cascade, thereby increasing ATP synthesis and restoring neuronal energy balance [92].

AMP also participates in an alternative MB pathway: it is converted to cAMP by adenylate cyclase, activating protein kinase A (PKA). PKA then phosphorylates CREB, which binds to the PGC-1α promoter to induce its expression, initiating MB through the cAMP/PKA/CREB pathway [93]. SIRT1, a NAD⁺-dependent deacetylase, acts as a parallel energy sensor: increased NAD⁺/NADH ratios during energy stress activate SIRT1, which deacetylates and activates PGC-1α [94]. Importantly, AMPK and SIRT1 pathways are interconnected: AMPK enhances NAD⁺ synthesis via nicotinamide phosphoribosyltransferase (NAMPT), elevating the NAD⁺/NADH ratio to activate SIRT1, which further activates PGC-1α. This AMPK/SIRT1/PGC-1α axis synergistically upregulates NRF1/2, amplifying MB [95], underscoring the integration of energy-sensing pathways in maintaining mitochondrial homeostasis.

Other factors

Beyond the core AMPK/PGC-1α axis, Ca²⁺ signaling and the mammalian target of rapamycin (mTOR) play significant roles in MB regulation. Elevated intracellular Ca²⁺ activates calcium/calmodulin-dependent protein kinase (CaMK), which either phosphorylates p38 mitogen-activated protein kinase (p38 MAPK) or upregulates the expression of cAMP response element-binding protein (CREB), both converging on PGC-1α activation via the Ca²⁺/p38 MAPK/PGC-1α pathway [96]. mTOR forms two distinct complexes: mTORC1 and mTORC2. mTORC1 regulates MB through Sestrin2, which inhibits mTORC1 under oxidative stress to preserve mitochondrial function [97]. It also stimulates synthesis of nuclear-encoded mitochondrial proteins by promoting ribosomal biogenesis [98]. Emerging evidence identifies non-canonical regulators, including miR-142-3p (which represses PGC-1α translation), tumor necrosis factor-related protein 3 (TWEAK, which activates PGC-1α via NF-κB), and adenosine receptor A1 (A1AR, which inhibits cAMP/PKA signaling to suppress MB) [[99], [100], [101]]. These factors add complexity to MB regulation, enabling context-specific tuning of mitochondrial mass in response to cellular cues.

Mitophagy

Concept and canonical process of mitophagy

In 2005, Lemasters first introduced the concept of mitophagy, describing it as a key selective autophagic process in which damaged or senescent mitochondria are encapsulated by autophagosomes and degraded into amino acids, fatty acids, and other small molecules for recycling, thus maintaining organelle homeostasis, cellular metabolic balance, and energy supply. Under physiological conditions, basal mitophagy ensures timely recognition and clearance of dysfunctional mitochondria, providing essential substrates for newly formed mitochondria via MB, sustaining ATP production, and maintaining intracellular redox balance. Conversely, impaired mitophagy leads to the accumulation of defective mitochondria, causing reduced ATP synthesis, excessive ROS generation, and subsequent oxidative damage to proteins, lipids, and nucleic acids, ultimately promoting neuronal apoptosis, a key pathological feature of CRCI.

Canonical mitophagy progresses through four sequentially ordered key steps (Fig. 2): i) Mitochondrial depolarization: Stimuli such as chemotherapy-induced oxidative stress, energy crisis, or cellular aging trigger loss of mitochondrial membrane potential (ΔΨm) in dysfunctional mitochondria; ii) Mitophagosome formation: Damaged mitochondria are enveloped by double-membraned autophagosomes, forming mitophagosomes; iii) Lysosomal fusion: Mitophagosomes fuse with lysosomes; iv) Mitochondrial degradation: Lysosomal hydrolases (e.g., cathepsins) degrade mitochondrial contents, enabling recycling of metabolites (e.g., amino acids) for cellular biosynthesis [102].

Fig. 2.

Molecular mechanisms of ubiquitin-dependent and ubiquitin-independent mitophagy (FUNDC1, FUN14 domain-containing protein 1; GP78, glycoprotein 78; LC3, microtubule-associated protein 1 light chain 3; MUL1, mitochondrial ubiquitin ligase 1; NDP52, nuclear dot protein 52 kDa; NIX/BNIP3, Bcl-2/adenovirus E1B 19 kDa-interacting protein 3/3 L; OPTN, optineurin; ROS, reactive oxygen species; SMURF1, SMAD ubiquitination regulatory factor 1; TBK1, TANK-binding kinase 1; ULK1, Unc-51 like autophagy activating kinase 1;).

At the molecular level, mitophagy can be initiated via two principal pathways: ubiquitin (Ub)-dependent and Ub-independent mechanisms. The most well-characterized ubiquitin-dependent pathway is mediated by the PINK1/Parkin axis, whereas Ub-independent mitophagy is further subdivided into receptor-mediated and lipid-mediated types, both of which play context-dependent roles in neuronal mitochondrial quality control [103].

Molecular mechanisms of mitophagy

Ubiquitin-dependent mitophagy

The PTEN-induced putative kinase 1 (PINK1)/E3 ubiquitin ligase Parkin pathway is the most thoroughly characterized Ub-dependent mitophagy pathway and its dysregulation is closely linked to chemotherapy-induced neuronal mitochondrial dysfunction. PINK1, encoded by the PARK6 gene, is a mitochondrial serine/threonine kinase crucial for mitochondrial quality control [104]. In healthy mitochondria with intact ΔΨm, PINK1 is imported across the inner mitochondrial membrane (IMM) via the TIM23 complex, cleaved by the IMM protease PARL (presenilin-associated rhomboid-like protein), and subsequently degraded by the proteasome, resulting in low steady-state cytoplasmic PINK1 levels [105]. However, upon mitochondrial damage (e.g., cisplatin-induced mtDNA damage) and loss of ΔΨm, PINK1 import is blocked, leading to PINK1 accumulation and oligomerization on the OMM, where it phosphorylates multiple OMM substrates [106].

Parkin, encoded by the PARK2 gene, is a RING-finger E3 ubiquitin ligase that ubiquitinates substrate proteins to target them for degradation [107]. In healthy cells, Parkin resides in the cytosol in an autoinhibited state, stabilized by intramolecular interactions between its Ubl (ubiquitin-like) and RING2 domains. Upon mitochondrial damage, PINK1 activates Parkin through two synergistic mechanisms: i) direct phosphorylation of Parkin at Ser65 in its ubiquitin-like domain (pSer65-Parkin); and ii) phosphorylation of ubiquitin molecules (pSer65-Ub) on OMM proteins, which then binds to Parkin’s Ubl domain and allosterically relieves autoinhibition [108]. This dual activation ensures high specificity for damaged mitochondria, avoiding unnecessary clearance of healthy organelles.

Activated Parkin translocates to the OMM, where it initiates a feed-forward amplification loop: it ubiquitinates OMM proteins (e.g., Mfn1/2, VDAC1) to generate K48- and K63-linked ubiquitin chains, K48 chains target proteins for proteasomal degradation (e.g., Mfn2, removing mitochondrial fusion capacity), while K63 chains recruit autophagy receptors [109]. The best-characterized autophagy receptor in this pathway is sequestosome-1 (p62/SQSTM1), which binds K63-linked ubiquitin chains via its ubiquitin-associated (UBA) domain and interacts with autophagy-related protein LC3/ATG8 via its LC3-interacting region (LIR). p62/SQSTM1 also undergoes self-oligomerization through its PB1 domain, facilitating the clustering of ubiquitinated mitochondria and their delivery to autophagosomes. Notably, p62/SQSTM1 levels inversely reflect autophagic activity, and the accumulation of p62/SQSTM1 is a classic marker of mitophagy impairment, as observed in CRCI models [110].

Phosphorylated ubiquitin chains (pSer65-Ub) on the OMM further recruit autophagy receptors optineurin (OPTN) and NDP52, which play non-redundant roles: OPTN binds pSer65-Ub via its UBAN domain and is phosphorylated by TBK1 at Ser177 to enhance its affinity for LC3, while NDP52 interacts with both pSer65-Ub and LC3 to bridge damaged mitochondria and autophagosomes [111]. Importantly, OPTN and NDP52 can translocate to the OMM independent of Parkin, highlighting their critical roles in Parkin-deficient neurons [112,113]. Additionally, Parkin-assembled K63 ubiquitin chains recruit the TBK1 kinase complex, which phosphorylates OPTN and NDP52 to further amplify the mitophagy signal, creating a second amplification loop that ensures efficient clearance of damaged mitochondria.

Genetic studies confirm PINK1 acts upstream of Parkin: Parkin overexpression can rescue mitochondrial dysfunction in PINK1-deficient cells, but PINK1 overexpression fails to compensate for Parkin deficiency [114,115]. Thus, the PINK1/Parkin axis functions as a hierarchical cascade, and deficiency in either protein (e.g., due to chemotherapy-induced transcriptional repression) disrupts mitophagy, leading to accumulation of damaged mitochondria in neurons.

Beyond PINK1/Parkin, other E3 ubiquitin ligases, including MUL1, FKBP8, and AMBRA1, mediate Ub-dependent mitophagy in a Parkin-independent manner, providing functional redundancy [116,117]. MUL1 (mitochondrial ubiquitin ligase 1) localizes to the OMM and ubiquitinates Mfn2, inhibiting mitochondrial fusion and promoting mitophagy; MUL1 deficiency increases Mfn2 activity, triggering mitochondrial hyperfusion and acting as a mitophagy tethering antagonist [118]. FKBP8 (FK506-binding protein 8) contains a LIR motif that mediates direct interaction with LC3, and this activity of FKBP8, together with its LIR motif, is required for mitophagy-induced mitochondrial fragmentation [119]. ATAD3A (ATPase family AAA domain-containing protein 3A), a transmembrane protein, mediates the mitochondrial import and degradation of PINK1. Its overexpression (observed in cisplatin-treated neurons) accelerates PINK1 degradation, suppressing mitophagy [120].

Ubiquitin-independent mitophagy

Ubiquitin-independent mitophagy occurs through receptor- or lipid-mediated mechanisms, which are particularly critical in neurons due to their high mitochondrial density and metabolic demand.

Receptor-mediated mitophagy relies on OMM proteins with conserved LIR motifs that directly bind LC3, bypassing the need for ubiquitination. Key receptors include NIX (BNIP3L), BNIP3 (Bcl-2/adenovirus E1B 19 kDa-interacting protein 3), and FUNDC1 (FUN14 domain-containing protein 1). These receptors are transcriptionally upregulated under stress conditions: NIX/BNIP3 are induced by HIF-1α during hypoxia (e.g., chemotherapy-induced microvascular dysfunction), while FUNDC1 is activated by hypoxic or oxidative stress [121,122]. Genetic deletion of NIX/BNIP3 or FUNDC1 in rodent models results in significant mitophagy impairment, increased neuronal ROS levels, and exacerbated CRCI-like cognitive deficits. FUNDC1 activity is further regulated by post-translational modifications: phosphorylation at Ser13 by CK2 (casein kinase 2) inhibits its LC3-binding capacity, while dephosphorylation by PGAM5 (phosphoglycerate mutase 5) or phosphorylation at Ser17 by ULK1 enhances it, creating a dynamic regulatory switch for mitophagy [123]. Additionally, FUNDC1 can be degraded via MARCH5 (an E3 ubiquitin ligase) in a Ub-dependent manner, linking Ub-dependent and -independent pathways [123].

Lipid-mediated mitophagy involves phospholipids and IMM proteins that act as “lipid receptors” for LC3. Cardiolipin (CL), a phospholipid exclusively localized to the IMM under physiological conditions, translocates to the OMM upon mitochondrial damage (e.g., doxorubicin-induced lipid peroxidation). Oxidized CL (ox-CL) directly binds the LIR-like motif of LC3, with higher affinity than non-oxidized CL, promoting mitophagy in hippocampal neurons [124,125]. Prohibitin 2 (PHB2), an IMM chaperone protein, functions as a secondary lipid-associated receptor: upon OMM rupture (a late stage of mitochondrial damage), PHB2 is exposed to the cytoplasm, binds LC3 via its LIR motif, and mediates clearance of severely damaged mitochondria [126]. Notably, PHB2-dependent mitophagy requires prior CL translocation, suggesting a hierarchical relationship where CL initiates clearance, and PHB2 ensures complete degradation of irreparably damaged organelles. The competitive interactions and regulatory hierarchies among these lipid receptors and LC3 isoforms (LC3A/B/C) in neurons remain to be fully elucidated, representing a key area for future CRCI research.

Mitochondrial Dynamics

Concept and canonical process of mitochondrial dynamics

Mitochondrial dynamics, a key continuous interplay between fusion and fission, is crucial for maintaining mitochondrial health and function [127]. Fusion enables the exchange of mitochondrial contents, effectively diluting localized damage and promoting complementation between partially dysfunctional mitochondria, restoring their metabolic capacity. Fission, by contrast, facilitates two key processes (Fig. 3): i) segregation of irreparably damaged mitochondrial fragments for targeted clearance via mitophagy; and ii) generation of small, transport-competent mitochondria to support regional energy demands. This dynamic equilibrium is essential for optimal mitochondrial function and cellular homeostasis, particularly in chemotherapy-sensitive neurons, post-mitotic cells with high energy requirements and polarized structures (somas, dendrites, axons) that rely on efficient mitochondrial transport.

Fig. 3.

Molecular mechanisms of mitochondrial fusion and fission (DNM2, dynamin 2; DRP1, dynamin-related protein 1; ER, endoplasmic reticulum; Fis1, fission 1; IMM, inner mitochondrial membrane; MFN1/2, mitofusins 1/2; MFF, mitochondrial fission factor; MiD49/51, mitochondrial dynamics proteins 49/51; OMM, outer mitochondrial membrane; OPA1, optic atrophy 1).

Recent studies have expanded the concept of mitochondrial dynamics beyond intracellular morphological changes to encompass intercellular mitochondrial transfer along cytoskeletal networks and between cells [128]. This broadened perspective integrates three core processes: mitochondrial fusion, fission, and intercellular transfer, as integral components of mitochondrial dynamics, highlighting their coordinated roles in maintaining tissue-level mitochondrial homeostasis, especially in the chemotherapy-exposed CNS.

Molecular mechanisms of mitochondrial dynamics

Mitochondrial fission

Mitochondrial fission is the process by which a single mitochondrion divides into two or more distinct daughter organelles, a process critical for mitochondrial quality control and spatial distribution. In mammals, fission is primarily orchestrated by dynamin-related protein 1 (DRP1), a cytosolic GTPase recruited to the outer mitochondrial membrane (OMM) via OMM-localized adaptor proteins [129]. These adaptors exhibit functional specialization: mitochondrial fission factor (MFF) is the primary recruiter of DRP1, with high affinity for the GTP-bound (active) form of DRP1 [130]; mitochondrial dynamics proteins of 49 and 51 (MiD49/51) play secondary roles, particularly in stress-induced fission [131]; and Fis1, once considered a core adaptor, has a debated role in mammals, with genetic deletion studies showing minimal impact on baseline fission (unlike essential role in yeast) [132].

The fission process involves a series of coordinated steps: i) ER-mediated pre-constriction: Endoplasmic reticulum (ER) tubules form contact sites with mitochondria (termed ER-mitochondria contact sites, or MERCs), marking the future division plane. This interaction is mediated by proteins like inverted formin 2 (INF2) and Spire1C, which induce actin nucleation and polymerization at MERCs, generating mechanical force to initiate mitochondrial constriction [133]; ii) DRP1 recruitment and oligomerization: ER-mediated constriction reduces mitochondrial diameter from 300 to 500 nm to approximately 150 nm, enabling MFF/MiD proteins to recruit DRP1 to the OMM. DRP1 then oligomerizes into a ring-like structure around the constricted site, with GTP hydrolysis driving further constriction [134,135]. iii) Membrane scission: Dynamin 2 (DNM2), a classical dynamin family member, is recruited to the DRP1 ring to complete scission of both OMM and IMM [136]. However, this step remains controversial: some studies demonstrate that DRP1 alone possesses intrinsic membrane-severing capacity (via GTP-driven conformational changes), rendering DNM2 dispensable for fission in neurons (where DNM1, not DNM2, is the dominant dynamin isoform) [137]. Following fission, daughter mitochondria face three fates: i) integration into the mitochondrial network via fusion; ii) targeted for mitophagy; or iii) transported to energy-demanding sites to support local ATP production.

Mitochondrial fusion

Mitochondrial fusion, the merging of two adjacent mitochondria, requires coordinated fusion of both the OMM and inner mitochondrial membrane (IMM), mediated by three dynamin-related GTPases with distinct subcellular localization and functions.

OMM fusion is driven by mitofusins 1 and 2 (MFN1/2), integral OMM proteins with a GTPase domain, two transmembrane domains, and heptad repeat regions (HR1/HR2). MFN1/2 are broadly expressed, but MFN2 is enriched in neurons, where it also regulates MERC formation (linking fusion to calcium homeostasis) [138]. OMM fusion proceeds via: i) homotypic (MFN1-MFN1 or MFN2-MFN2) or heterotypic (MFN1-MFN2) dimerization of HR2 domains across adjacent mitochondria; ii) GTP hydrolysis-induced conformational changes in the GTPase domain; and iii) membrane merging, facilitated by the hydrophobic transmembrane domains.

IMM fusion is mediated by optic atrophy protein 1 (OPA1), a soluble IMM-associated protein processed into two isoforms: long (L-OPA1, membrane-anchored) and short (S-OPA1, soluble in the intermembrane space) [139]. Processing is catalyzed by two proteases: PARL (IMM-localized) cleaves l-OPA1 to generate S-OPA1 under basal conditions, while YME1L (IMM-localized AAA protease) degrades excess S-OPA1 to maintain isoform balance. l-OPA1 is universally required for IMM fusion, while S-OPA1’s role is context-dependent: it is dispensable for fusion but critical for maintaining cristae structure (via interaction with the MICOS complex) and preserving OXPHOS activity.

Cardiolipin (CL), a negatively charged phospholipid unique to the IMM, plays a non-redundant role in IMM fusion: l-OPA1 binds CL via its amphipathic helix, with CL neutralizing l-OPA1’s positive charge to promote oligomerization. These l-OPA1-CL oligomers generate mechanical force to drive IMM merging [140]. Importantly, OMM fusion mediated by MFN1 is a prerequisite for IMM fusion: MFN1-dependent OMM docking brings IMMs into close proximity (∼10 nm), enabling l-OPA1-CL interactions [141]. This interdependence ensures synchronized fusion of both membranes, avoiding formation of non-functional “mitochondrial ghosts” (OMM-enclosed vesicles lacking IMM content).

Mitochondrial transfer

Mitochondrial transfer refers to the translocation of mitochondria between cells (intercellular) or within a single cell (intracellular), a process increasingly recognized as a key mechanism of mitochondrial homeostasis in the CNS [142]. Intercellular mitochondrial transfer occurs via three primary mechanisms: i) Tunneling nanotubes (TNTs): Thin, actin-based protrusions (50–200 nm diameter) that connect adjacent cells, enabling direct transfer of mitochondria. In the CNS, astrocytes use TNTs to transfer healthy mitochondria to chemotherapy-damaged neurons, restoring their ATP production [143]; ii) Extracellular vesicles (EVs): Mitochondria are packaged into EVs (e.g., microvesicles, exosomes) and released by donor cells (e.g., microglia, astrocytes). Recipient neurons internalize these EVs via endocytosis, and the transferred mitochondria are released into the cytosol to integrate into the host mitochondrial network [144]; iii) Cell fusion: Rare in the adult CNS, but observed in neural stem cells, where fusion with damaged neurons facilitates mitochondrial replacement [145]. and other specialized structures. Donor cells actively release mitochondria, which are then internalized by recipient cells and integrated into their mitochondrial network or targeted for degradation [143]. Intracellular mitochondrial transport relies on microtubules and associated motor proteins, particularly in neurons. Mitochondrial Rho GTPases 1 and 2 (Miro1/2) are key regulators of this process [146]. Miro1 interacts with kinesin family member 5 (KIF5), anchoring mitochondria to microtubules and facilitating their transport. Miro1 overexpression enhances mitochondrial transfer efficiency, restoring mitochondrial membrane potential and ATP production in recipient cells [147].

Physiologically, mitochondrial transfer maintains tissue homeostasis; pathologically, it ameliorates mitochondrial dysfunction in CRCI: a preclinical study show that enhancing astrocyte-to-neuron mitochondrial transfer (via Miro1 overexpression) reduces chemotherapy-induced neuronal death and improves cognitive function [148].

Mitochondrial proteostasis

Concept and physiological significance of mitochondrial proteostasis

Mitochondrial proteostasis refers to the dynamic maintenance of the mitochondrial protein landscape through coordinated regulation of protein folding, assembly, import, and degradation [149]. As semiautonomous organelles with dual genetic origins (nuclear and mitochondrial genomes), mitochondria face continuous proteotoxic challenges arising from oxidative damage, incorrect assembly, or aberrant folding of both nuclear- and mitochondrial-encoded proteins [76]. The integrity of these processes is essential for maintaining mitochondrial function, cellular metabolism, and overall viability, especially under stress conditions such as those encountered during chemotherapy, which exacerbates proteotoxicity by disrupting mtDNA replication and protein synthesis [150].

To preserve mitochondrial protein homeostasis across distinct compartments (outer membrane, intermembrane space, inner membrane, and matrix) (Fig. 4), a multilayered surveillance network operates seamlessly, integrating local quality control with organelle-wide adaptive responses [6]. Failure of mitochondrial proteostasis drives the accumulation of misfolded proteins, leading to mitochondrial dysfunction, neuronal apoptosis, and cognitive impairment, pathologies directly linked to CRCI [151,152]. This underscores proteostasis as a critical MQC node in chemotherapy-induced neurotoxicity.

Fig. 4.

Compartment-specific mitochondrial proteostasis systems (ABC transporter: ATP -binding cassette transporter; ATP23, adenosine triphosphate; CLPXP, ; HTRA2, HtrA Serine Peptidase 2; LONP1, lon peptidase 1, mitochondrial).

Molecular mechanisms of mitochondrial proteostasis

Compartment-specific protein surveillance and degradation

Outer mitochondrial membrane (OMM): ubiquitin-proteasome system (UPS)

At the OMM, the UPS is the primary machinery for degrading misfolded, damaged, or unassembled mitochondrial proteins. Unlike other mitochondrial compartments, the OMM relies on cytosolic proteasomes (26S) for degradation, as the membrane lacks intrinsic proteolytic activity [153,154]. This process is mediated by OMM-localized E3 ubiquitin ligases, including Parkin (critical for mitophagy-linked degradation), MUL1 (targets fusion protein Mfn2), and RNF185 (degrades misfolded VDAC1) [155]. These ligases conjugate K48-linked ubiquitin chains to substrate proteins, marking them for proteasomal degradation, preventing toxic aggregation and serving as a quality checkpoint for mitophagy initiation [156,157]. Notably, chemotherapy inhibits RNF185 activity, leading to VDAC1 accumulation and OMM permeability, exacerbating neuronal mitochondrial dysfunction [158].

Intermembrane space (IMS): HtrA2/Omi protease pathway

Within the IMS, the serine protease HtrA2/Omi is a central quality control component. Unlike the UPS-dependent OMM, the IMS lacks proteasomal access, making HtrA2/Omi essential for degrading misfolded, unassembled, or mislocalized proteins primarily within the IMS [159,160]. HtrA2/Omi’s proteolytic activity is redox-regulated: its active-site cysteine is oxidized by chemotherapy-induced ROS, reducing protease function and promoting IMS protein aggregation. Dysfunction of this pathway is directly linked to CRCI: HtrA2/Omi knockout mice exhibit enhanced cisplatin-induced neuronal loss and cognitive deficits, which are reversed by HtrA2/Omi overexpression [161,162].

Inner mitochondrial membrane (IMM): AAA+ proteases i-AAA and m-AAA

Two highly conserved ATP-dependent AAA+ (ATPases associated with diverse cellular activities) proteases, including i-AAA and m-AAA, maintain IMM proteostasis. i-AAA (Yme1L in mammals), with its catalytic domain facing the IMS, extracts and degrades misfolded or damaged proteins from the IMM, IMS, and even OMM [163]. m-AAA (paraplegin-SPG7 complex), oriented toward the matrix, targets misfolded IMM and matrix proteins and is critical for ETC complex assembly and mitochondrial translation fidelity [164,165]. Chemotherapy reduces Yme1L expression by repressing the transcription factor NRF1, impairing degradation of oxidized IMM proteins and promoting ETC dysfunction in hippocampal neurons.

Mitochondrial matrix: LonP1 and ClpXP proteolytic systems

The matrix relies on two ATP-dependent proteases: LonP1 and ClpXP. LonP1, a serine protease, eliminates oxidatively modified or misfolded matrix proteins and regulates mtDNA replication by degrading damaged mtDNA polymerase γ [166]. Chemotherapy induces LonP1 hyperactivation via ROS, leading to excessive degradation of essential matrix proteins and disrupting protein folding [166]. The ClpXP complex (composed of ClpX ATPase and ClpP protease) specifically degrades unfolded proteins that fail to associate with chaperones such as HSP60, HSP10, and HSP70, and restrains mtUPR activation under basal conditions by degrading misfolded proteins before they accumulate [167,168]. Reduced ClpP expression in cisplatin-treated neurons causes mtUPR overactivation, triggering neuronal apoptosis.

Mitochondrial unfolded protein response (mtUPR): an adaptive signaling axis

mtUPR activation and transcriptional reprogramming

First identified in mammalian cells but best characterized in C. elegans, the mtUPR was an evolutionarily conserved adaptive pathway that senses mitochondrial proteotoxic stress and orchestrates nuclear gene expression to restore organellar proteostasis [169]. Diverse insults, including chemotherapy-inhibition of mitochondrial translation, mtDNA depletion, chaperone/protease dysfunction, ETC defects, activate the mtUPR [170,171]. The core mediator in mammals is ATF5, which contains both mitochondrial targeting sequences (MTS) and nuclear localization sequences (NLS). Under basal conditions, ATF5 is imported into the mitochondria and rapidly degraded by LonP1 in the matrix [172]. Upon chemotherapy-induced mitochondrial stress, ATF5 import is impaired, leading to cytosolic accumulation and nuclear translocation. In the nucleus, ATF5 binds to the UPRE (unfolded protein response element) in promoters of target genes, upregulating: i) mitochondrial chaperones (HSPD1, HSPA9); ii) proteases (LONP1, CLPP); iii) ROS detoxification enzymes (SOD2, GPX4); and iv) glycolysis regulators (PFKFB3), compensating for OXPHOS dysfunction [173].

Chromatin remodeling and epigenetic modulation

ATF5 drives only ∼40% of mtUPR-induced transcripts, indicating parallel regulatory pathways. Epigenetic regulators play key roles: JMJD-1.2/Phf8 (histone demethylase) removes repressive H3K9me2 marks from mtUPR gene promoters, while JMJD3.1/Jmjd3 demethylates H3K27me3 to enhance chromatin accessibility [174]. Additionally, the transcription factor DVE-1 and cofactor UBL-5 form a complex that recruits histone acetyltransferases to mtUPR promoters, further boosting transcription. Chemotherapy downregulates Phf8, increasing H3K9me2 at the HSPD1 promoter and blunting mtUPR activation, exacerbating CRCI [175,176].

Integrated stress response and mammalian mtUPR complexity

In mammals, mtUPR is coordinated with the integrated stress response (ISR) to fine-tune adaptation. The ISR kinase PERK (activated by ER stress or mitochondrial ROS) phosphorylates eIF2α, reducing global translation but selectively enhancing ATF4 translation. ATF4 then cooperates with ATF5 to upregulate mtUPR genes [177,178]. Moreover, compartment-specific UPR programs exist: the IMS-specific UPR (mediated by CHCHD4, coiled-coil-helix-coiled-coil-helix domain-containing protein 4) responds to IMS proteotoxicity by upregulating IMS chaperones (e.g., COX17), while the matrix UPR (ATF5-dependent) targets matrix proteins [179]. Cisplatin specifically impairs the IMS-specific UPR by reducing CHCHD4 expression, leading to IMS protein aggregation in neurons.

Physiological impact and contextual outcomes

The mtUPR exhibits context-dependent effects in neurons: moderate activation (e.g., transient chemotherapy exposure) enhances neuronal stress resistance by restoring proteostasis, while chronic or excessive activation triggers pro-apoptotic signaling [180]. In CRCI models, mice with neuron-specific ATF5 knockout show more severe cognitive deficits, while mild ATF5 overexpression rescues chemotherapy-induced mitochondrial dysfunction and memory impairment [181]. This highlights the mtUPR as a “double-edged sword” and a potential therapeutic target for CRCI.

Mitochondrial-derived vesicles

Mitochondria-derived vesicles (MDVs) have recently been recognized as a crucial component of the MQC network, providing a rapid and selective response to mitochondrial stress that precedes mitophagy [182]. The existence and characteristics of MDVs were first reported by Neuspiel et al. in 2008 using HeLa and COS7 cell models, who described MDVs as either single-membrane structures originating from the OMM or double-membrane vesicles that incorporate both inner and outer membrane components along with matrix cargo [183]. Key characteristics distinguishing MDVs include their small diameter (typically 70-150 nm), selective cargo packaging, and initially reported independence from the canonical mitochondrial fission protein Dynamin-related protein 1 (DRP1) during their formation [184]. Subsequent studies have identified MDVs in various tissues and physiological contexts, including cardiomyocytes, and skeletal muscle cells affected by disease, and notably in hippocampal and cortical neurons [185], underscoring their relevance to CRCI pathogenesis.

Growing evidence positions MDVs as an early-acting triage mechanism within the MQC network, preceding the activation of bulk mitophagy [186]. Research indicates that upon initial mitochondrial damage or stress, MDV formation is rapid, occurring within minutes, suggesting a swift response to focal insults [187]. In contrast, robust activation of canonical mitophagy, which involves sequestration of entire mitochondria by autophagosomes, typically requires more severe or sustained stress and may not be fully engaged until hours later [188]. This temporal difference, coupled with the observed independence of MDV formation from core autophagy-related genes (ATGs) like ATG5 and the mitochondrial fission machinery (DRP1), strongly suggests that MDVs represent a parallel and mechanistically distinct pathway for maintaining mitochondrial homeostasis [183,189]. This pathway allows for the selective packaging and removal of specific damaged proteins or lipids while preserving the bulk of the organelle, thereby preventing the premature degradation of potentially salvageable functional mitochondria, a critical advantage for post-mitotic neurons with limited mitochondrial renewal capacity.

The molecular mechanisms governing MDV biogenesis and cargo sorting are complex and actively being elucidated (Fig. 5). Central regulators in this process include the Parkinson’s disease-associated proteins PTEN-induced PINK1 and Parkin. The PINK1/Parkin pathway is well-established for its role in initiating mitophagy upon severe mitochondrial depolarization; however, it also plays a critical role in mediating the formation of selective cargo-containing MDVs under mild stress [188,190]. Upon mitochondrial damage, PINK1 accumulates on the OMM. While severe global depolarization triggers full mitophagy, more localized or specific insults lead to restricted PINK1 accumulation, which is sufficient to recruit and activate Parkin [191]. Parkin, in turn, ubiquitinates specific OMM proteins destined for packaging into MDVs. These vesicles then bud off the mitochondria and are targeted to lysosomes for degradation [192]. This selective removal of damaged components, such as specific subunits of the ETC or chaperones, via Parkin-mediated MDVs is hypothesized to maintain the overall integrity of the remaining mitochondrial network [188]. Genetic studies support the critical role of PINK1/Parkin in MQC. Neuron-specific PINK1 knockout mice exhibit reduced MDV formation, increased mitochondrial ETC subunit aggregation, and worse cisplatin-induced memory impairment compared to wild-type littermates, while Parkin deficiency abolishes MDV-dependent clearance of ox-CL in cortical neurons [193,194].

Fig. 5.

Mitochondria-derived vesicles as an early MQC triage mechanism (MAPL, mitochondria-associated protein ligase; TOMM20, translocase of outer mitochondrial membrane 20; PDH, pyruvate dehydrogenase; Rab7/9, Ras-Associated Protein 7/9).

Mechanistically, the localized accumulation of PINK1 and subsequent Parkin activation on the OMM can be triggered by specific stress signals, including localized production of ROS and oxidation of CL [195]. CL, a phospholipid uniquely enriched in the IMM, is highly susceptible to peroxidation by chemotherapy-induced ROS [196]. This ROS/CL-mediated local signaling aligns with the observation that MDVs can form in response to localized stress and do not necessarily require complete mitochondrial depolarization [197]. Furthermore, while PINK1/Parkin initiates the ubiquitination signal, the membrane scission machinery involved in pinching off MDVs appears to differ from canonical DRP1-dependent fission [198].

In addition to the PINK1/Parkin axis, other protein machineries are implicated in MDV formation. Recent studies highlight the involvement of sorting nexin 9 (SNX9), a BAR-domain-containing protein that interacts with endocytic components like Dynamin, Adaptin-2 (AP-2), and Clathrin [199]. SNX9 localizes to PINK1-enriched OMM foci, where its BAR domain induces membrane bending, and its SH3 domain recruits Dynamin to mediate neck constriction, facilitating MDV budding and release. SNX9 also contributes to MDVs involved in mitochondrial antigen presentation, but its role in neuronal MDVs is distinct [200]. In hippocampal neurons, SNX9 is required for MDV-mediated clearance of misfolded matrix proteins (e.g., LonP1 substrates), and chemotherapy (paclitaxel) reduces SNX9 expression by repressing the transcription factor CREB, impairing this process. However, the precise mechanism by which SNX9 coordinates with PINK1/Parkin to select cargo and its role in different MDV subtypes require further investigation.

Disruption of MQC by chemotherapeutic agents in CRCI

Chemotherapy is a cornerstone in the treatment of various cancers, but its clinical utility is limited by off-target toxicities, among which neuronal MQC disruption is a key driver of CRCI. Chemotherapeutic agents, such as doxorubicin and cisplatin, directly target mitochondrial structure and function, triggering a cascade of MQC failures that culminate in neuronal dysfunction and cognitive decline (Table 1). For instance, doxorubicin induces oxidative stress via ROS overproduction, damaging mtDNA and proteins; this not only impairs OXPHOS but also disrupts MQC processes critical for neuronal survival [201]. Similarly, cisplatin causes mtDNA adduct formation and inhibits mitochondrial proteases, leading to misfolded protein accumulation and MQC collapse, effects that are particularly detrimental to hippocampal neurons, which rely on intact mitochondria for synaptic plasticity [202]. Collectively, chemotherapy-induced MQC disruption drives impaired ATP production, excessive ROS, and neuronal cell death, forming the pathological basis of CRCI [203,204].

Table 1.

Chemotherapeutic agents and their mechanisms of mitochondrial quality control dysregulation in chemotherapy-related cognitive impairment.

Chemotherapeutic Agent	Primary Molecular / Cellular Action Leading to MQC Dysregulation	Dysregulated MQC	Consequences on MQC and Downstream Effects
Doxorubicin	- Intercalates into mtDNA, inhibits mtDNA replication and transcription. - Redox cycling, leading to direct and indirect reactive oxygen species overproduction. - Impairs mitochondrial calcium buffering capacity.	Biogenesis, Mitophagy, Dynamics, Proteostasis	- Biogenesis: Deficits in electron transport chain (ETC) subunit synthesis (from mtDNA damage), reduced PGC-1α activity (indirect). - Dynamics: TLR4/NF-κB signaling promotes excessive mitochondrial fission (increased p-DRP1Ser616/DRP1 ratio), leading to fragmentation and impaired axonal transport. - Mitophagy: Initiating factors (Parkin) are upregulated, but late-stage autophagic flux is blocked (decreased Beclin-1, p62 accumulation), leading to toxic accumulation of dysfunctional mitochondria. - Proteostasis: Oxidative damage to mitochondrial lipids, proteins, and mtDNA; potential impact on protease activity (implied by general mitochondrial damage and ROS). - General/Downstream: Severe bioenergetic failure (reduced oxygen consumption rate, TCA/ETC enzyme activity, ATP), sustained ROS production, mPTP opening, loss of mitochondrial membrane potential (ΔΨm), neuroinflammation (TNF-α, IL-1β, NLRP3 inflammasome activation), multi-modal neuronal death (apoptosis via MOMP, Bcl-2/Bax, caspase-3; necroptosis via RIPK1/RIPK3/MLKL; pyroptosis via GSDMD), synaptic loss, and inhibited hippocampal neurogenesis.
Cyclophosphamide	- Metabolized to acrolein, which inhibits nicotinamide phosphoribosyltransferase (NAMPT, rate-limiting enzyme in NAD+ biosynthesis). - Acrolein binds to and inactivates superoxide dismutase 2.	Biogenesis, Proteostasis, Mitophagy (implied), Dynamics (implied)	- Biogenesis: Reduced NAD+ levels (NAMPT inhibition) -> impaired mitochondrial biogenesis (indirect via PGC-1α axis), lowering NAD+/NADH ratio. - Proteostasis: Inactivation of SOD2 by acrolein -> increased mitochondrial ROS and oxidative stress. - Dynamics/Mitophagy (Inferred): Ultrastructural cristae damage (fracture, vacuolation, loss of density), mitochondrial swelling and vacuolation -> impaired ETC function, reduced ATP, leading to accumulation of dysfunctional mitochondria. - General/Downstream: Mitochondrial bioenergetic failure (reduced ATP, ETC Complex I/IV activity), oxidative stress (lipid peroxidation, GSH depletion), glial activation (M1 phenotype microglia) -> neuroinflammation (TNF-α, IL-1β), neuronal degeneration (cytoplasmic vacuolation, nuclear pyknosis).
Cisplatin	- Forms intrastrand/interstrand DNA adducts (mtDNA and nuclear DNA), suppresses mtDNA-encoded subunit expression. - Suppresses α-tubulin acetylation levels. - Impacts mitochondrial protease function.	Biogenesis, Dynamics, Proteostasis, Mitochondria-Derived Vesicles	- Biogenesis: Downregulation of PGC-1α -> insufficient new mitochondria, diminished repair capacity, exacerbates neurodegeneration. - Dynamics: Impaired α-tubulin acetylation (via HDAC6, DLK-JNK/c-Jun pathway activation) -> blocked axonal mitochondrial transport, inadequate mitochondrial supply to synapses. - Proteostasis: MtDNA damage, suppression of IMS-specific UPR by reducing CHCHD4 expression, leading to accumulation of misfolded IMS proteins and ETC dysfunction. - Mitochondria-Derived Vesicles: Parkin deficiency (implied by MQC disruption) abolishes MDV-dependent clearance of oxidized cardiolipin (ox-CL) in cortical neurons. - General/Downstream: Direct mitochondrial structural damage (swelling, OMM wrinkling, cristae disorganization), functional impairment (reduced MRC/SRC, ATP production, ΔΨm), ROS overproduction, neuroinflammation (TLR4/S1P axis, peroxynitrite), p53 translocation to mitochondria, cytochrome c release, caspase cascade (caspase-9, caspase-3) -> neuronal apoptosis, synaptic dysfunction, amyloid β/p-Tau deposition.
5-Fluorouracil	- Pyrimidine analog, direct damage to mtDNA.	Biogenesis, Dynamics	- Biogenesis: Inhibits PGC-1α expression -> hinders new mitochondrial generation and renewal. - Dynamics: Downregulation of fusion proteins (MFN2) and upregulation of fission proteins (FIS1) -> excessive mitochondrial fragmentation and swelling. - General/Downstream: Impaired ETC function, reduced ATP, oxidative stress (ROS, lipid peroxidation), inhibition of BDNF/Akt/Nrf2 and ERK/mTOR pathways -> aberrant dendritic spine morphology, reduced synaptic protein synthesis (PSD-95), synaptic dysfunction.
Vincristine	- Microtubule disruptor (stabilizes polymerized tubulin).	Dynamics (transport), Proteostasis (implied)	- Dynamics: Impaired axonal transport of mitochondria -> aberrant accumulation of mitochondrial ETC components in axons, localized ATP depletion. - Proteostasis: Accumulation of ETC components implies failure of local protein turnover/clearance systems. - General/Downstream: Impaired oxidative phosphorylation function, critical ATP depletion, ROS generation, activation of SARM1-mediated axonal degeneration pathway.
Temozolomide	- DNA-alkylating agent -> alkylation damage to mitochondrial DNA.	Biogenesis (mtDNA replication/transcription), Proteostasis (implied)	- Biogenesis: MtDNA alkylation damage, inhibition of mtDNA replication and transcription -> cumulative mtDNA lesions, reduced expression of ND1 and CytB. - Proteostasis: Impaired ETC leads to electron leakage and elevated ROS -> damage to mitochondrial proteins and lipids. - General/Downstream: Elevated ROS levels, triggering of intrinsic mitochondrial apoptotic pathway (increased caspase-9, caspase-3 expression) -> neuronal cell death or impaired function.
Busulfan	- Bifunctional alkylating agent -> direct induction of oxidative stress.	Proteostasis (antioxidant defense), Biogenesis (mtDNA integrity), Mitophagy (implied)	- Proteostasis: Severe oxidative stress (elevated malondialdehyde (MDA), glutathione (GSH) depletion, suppressed SOD/catalase (CAT) activity) -> mitochondrial membrane lipid peroxidation. - Biogenesis: MtDNA damage. - Mitophagy (Implied): Mitochondrial membrane lipid peroxidation and mtDNA damage lead to dysfunctional mitochondria that are not efficiently cleared. - General/Downstream: Inhibited mitochondrial ETC Complex II activity -> compromised oxidative phosphorylation, reduced ATP generation, impaired neuronal synaptic plasticity.

The link between MQC dysfunction and CRCI is uniquely critical in the CNS: neurons are post-mitotic, have high energy demands, and lack the ability to dilute mitochondrial damage via cell division. Chemotherapy-induced MQC failure thus leads to irreversible neuronal damage, with deficits in: i) mitochondrial biogenesis (reduced PGC-1α activity), limiting mitochondrial renewal; ii) mitophagy (blocked autophagic flux), causing damaged mitochondria accumulation; iii) dynamics (imbalanced fission/fusion), impairing mitochondrial transport to synapses; and iv) proteostasis (inhibited LonP1/ClpXP), promoting toxic protein aggregation [205]. The disruption of mitochondrial function in neurons can result in decreased energy production and increased susceptibility to oxidative stress, ultimately impairing synaptic plasticity and cognitive function [206]. Furthermore, these defects synergize with neuroinflammation to exacerbate synaptic loss and cognitive decline, creating a “feed-forward loop” where MQC dysfunction amplifies inflammation, and inflammation further disrupts MQC [207].

Doxorubicin

Doxorubicin (DOX), a first-line anthracycline chemotherapeutic agent, is highly effective against breast, lung, and hematological cancers. However, its dose-dependent off-target toxicities, including cardiotoxicity and neurotoxicity, significantly limit clinical application, with DOX-induced neurotoxicity directly driving CRCI in treated patients [208]. Accumulating preclinical and translational evidence identifies MQC disruption as the central mediator of DOX-induced neuronal injury, linking direct mitochondrial damage to downstream cognitive deficits [209].

Direct mitochondrial damage

DOX exerts initial neuronal toxicity by targeting mitochondria, leveraging its physicochemical properties to accumulate in the organelle. Due to its positive charge and amphipathic nature, DOX preferentially accumulates in the negatively charged mitochondrial matrix and can intercalate into mtDNA [210]. This intercalation impairs mtDNA replication and transcription, leading to deficits in the synthesis of essential mitochondrial proteins, particularly subunits of the ETC [211]. Furthermore, DOX is a potent inducer of ROS production, both directly through redox cycling and indirectly by disrupting the ETC [212]. Increased mitochondrial ROS contributes to oxidative damage of mitochondrial lipids, proteins, and mtDNA, creating a vicious cycle of oxidative stress and mitochondrial deterioration [213]. Studies in animal models have shown elevated systemic and brain oxidative stress markers following DOX treatment, which are significantly reduced in inflammatory mediator-deficient models like TNF-α knockout mice, suggesting a critical role for inflammation in mediating DOX-induced oxidative damage and subsequent mitochondrial dysfunction [214]. DOX treatment also impairs mitochondrial calcium buffering capacity, leading to mitochondrial calcium overload, which can trigger increased ROS production and heighten the sensitivity of the mitochondrial permeability transition pore (mPTP), further compromising membrane integrity and function [215].

Mitochondrial dynamics imbalance

Mitochondrial fission/fusion balance is essential for neuronal function, fission generates small, transport-competent mitochondria for synapses, while fusion dilutes localized damage. DOX disrupts this balance via TLR-4/MD-2/NF-κB-dependent signaling, creating a persistent pro-fission state [56]. While some studies indicate an increase in markers associated with mitochondrial fission via increased p-DRP1 (Ser616)/DRP1 ratio, suggesting enhanced fragmentation, others concurrently show increased levels of fusion proteins (Mfn1, Mfn2, OPA1), potentially reflecting a compensatory response or different cellular contexts [216]. This state of imbalanced or excessive fission/fusion, however, leads to fragmented mitochondria, impaired mitochondrial trafficking along axons, particularly critical in neurons, and ultimately contributes to synaptic dysfunction and degeneration [217].

Mitophagy failure

DOX triggers a “futile” mitophagy response, activating early signals to clear damaged mitochondria but blocking late-stage degradation, leading to toxic accumulation of dysfunctional organelles. While studies often report an upregulation of mitophagy initiating factors like Parkin following DOX exposure, suggesting an attempt to clear damaged mitochondria, concurrently observed markers indicative of impaired autophagic flux (e.g., decreased Beclin-1 expression and accumulation of the autophagic substrate p62) point towards a block in the later stages of the autophagic process [216]. This suggests that despite signals to initiate mitophagy, dysfunctional mitochondria are not efficiently cleared, leading to their accumulation and exacerbation of cellular damage.

Bioenergetic collapse and multi-modal neuronal death

The cumulative effect of direct damage and impaired MQC leads to severe mitochondrial bioenergetic failure in neurons. Dox treatment significantly reduces mitochondrial respiratory capacity, including basal, ATP-linked, maximal, and spare respiratory capacity, as measured by oxygen consumption rate (OCR) [218]. This is consistent with observed decreases in the activity of key enzymes in the tricarboxylic acid (TCA) cycle (e.g., ICDH, α-KGDH, SDH, MDH) and ETC complexes (Complexes I, III, IV) [[219], [220], [221]]. The resulting decline in ATP production compromises cellular energy supply essential for neuronal function, particularly at synapses [222].

Persistent mitochondrial ROS production via TNF-α and TLR-4/NLRP3 inflammasome activation [56,223,224], creates a cytotoxic environment. NLRP3 inflammasome activation, potentially triggered by mitochondrial DNA leakage into the cytosol [225], further propagates inflammatory responses via caspase-1 activation and subsequent release of pro-inflammatory cytokines and gasdermin D (GSDMD)-mediated pyroptosis.

Mitochondrial dysfunction acts as a central hub activating various programmed cell death pathways in neurons. Dox-induced changes in the Bcl-2/Bax ratio favor outer mitochondrial membrane permeabilization (MOMP), leading to the release of pro-apoptotic factors like cytochrome c into the cytosol, which activates the caspase cascade (e.g., caspase-3), culminating in apoptosis [218]. Elevated mitochondrial ROS can also trigger the activation of necroptosis through the RIPK1/RIPK3/MLKL pathway, characterized by plasma membrane rupture and release of cellular contents [225]. Furthermore, the inflammatory response mediated by mtDNA leak and NLRP3 activation can induce pyroptosis. These diverse cell death modalities contribute to the reduction in neuron numbers observed in affected brain regions like the hippocampus.

Synaptic loss and neurogenesis inhibition

The cumulative impact of impaired bioenergetics, oxidative stress, inflammation, and cell death pathways disrupts neuronal connectivity and plasticity [222]. DOX treatment leads to dendritic spine loss and impaired synaptic function. Furthermore, DOX inhibits neurogenesis in the hippocampal dentate gyrus, evidenced by reduced proliferation and survival of neural progenitor cells [226]. These effects on neuronal structure, function, and regeneration directly underlie the cognitive deficits observed in CRCI.

In summary, DOX disrupts all core MQC pathways in neurons. It causes direct mtDNA/ETC damage, induces oxidative stress cycling, imbalances mitochondrial dynamics, blocks mitophagy clearance, and collapses bioenergetics. These primary MQC defects act as a central hub, triggering downstream neuroinflammation, multi-modal neuronal death, synaptic loss, and reduced neurogenesis, collectively driving the pathogenesis of CRCI.

Cyclophosphamide

Cyclophosphamide (CTX), a bifunctional alkylating agent widely used in the treatment of breast cancer, lymphoma, and hematological malignancies, is a major contributor to CRCI, affecting 30–45% of patients, with deficits in short-term memory, spatial learning, and executive function persisting for 5+ years post-treatment [227,228]. Unlike DOX, which directly targets mitochondria via redox cycling, CTX exerts neurotoxicity primarily through its metabolic byproduct acrolein, a highly reactive aldehyde that crosses the BBB and accumulates in hippocampal and prefrontal cortical neurons, triggering MQC collapse and neuronal death [229].

Mitochondrial bioenergetic failure

Mitochondrial dysfunction is the cornerstone of CTX-induced neurotoxicity, with bioenergetic collapse driven by perturbed NAD⁺ metabolism and ETC impairment. CTX-derived acrolein irreversibly inhibits nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD⁺ biosynthesis, reducing hippocampal NAD⁺ levels and lowering the NAD⁺/NADH ratio [230]. The NAD⁺/NADH redox couple is pivotal for mitochondrial respiration and various metabolic pathways; its imbalance directly reflects impaired mitochondrial oxidative phosphorylation efficiency and altered overall redox state. This energy crisis likely exacerbates mitochondrial dysfunction, potentially by inhibiting processes like mitochondrial biogenesis, and has been closely linked to the dysregulation of the antioxidant Nrf-2/HO-1 axis [230].

At the molecular level, the impact of CTX (alone or in combination with DOX) on mitochondrial respiratory chain complex activity presents some complexity. Earlier studies reported that combined CTX and DOX treatment significantly inhibited Complex I and Complex IV activity in the brain, concurrently promoting ROS and lipid peroxidation generation and leading to glutathione (GSH) depletion [219]. These findings collectively point towards exacerbated mitochondrial oxidative stress and subsequent functional impairment. Another study similarly suggested that reduced mitochondrial Complex I activity and a slight increase in lipid peroxidation levels might underlie cognitive impairment following CMF (CTX, ethotrexate, 5-Fluorouracil) and methotrexate alone treatments [231]. However, conflicting reports exist, with some studies observing no significant impact of combined CTX and Dox on mitochondrial Complex I and IV activity [232]. Such seemingly contradictory results could be attributable to variations in treatment regimens (e.g., dosage, duration, and frequency) and the specific brain regions or cell types examined.

Mitochondrial antioxidant inactivation

CTX disrupts redox homeostasis via selective inhibition of mitochondrial antioxidant enzymes, distinct from DOX’s global ROS induction. CTX acrolein binds to the active site of superoxide dismutase 2 (SOD2), reducing its activity in hippocampal neurons [232]. DOX induces dose-dependent GSH depletion and enhances glutathione peroxidase (GSH-Px) activity as a compensatory response, while CTX has minimal effect on GSH/GSH-Px but specifically impairs SOD2. This suggests that CTX and DOX converge on mitochondrial oxidative stress but via distinct molecular targets, implying combination regimens may cause additive redox damage.

Glial cell-mediated amplification of mitochondrial injury

CTX indirectly exacerbates neuronal mitochondrial dysfunction via glial cell activation, creating a neuroinflammatory-mitochondrial feedback loop. CTX + epirubicin (an anthracycline analog of DOX) reduces microglial mitochondrial membrane potential (ΔΨm) and increases ROS production, triggering microglial polarization to the pro-inflammatory M1 phenotype [233]. Activated microglia release TNF-α and IL-1β, which bind to neuronal TNF-R1/IL-1R1 and activate NF-κB, further inhibiting neuronal SOD2 and promoting mPTP opening [234].

Ultrastructural mitochondrial damage and neuronal degeneration

Histopathological and ultrastructural analyses reveal CTX-induced hippocampal injury that is directly linked to mitochondrial structural collapse. CTX reduces the thickness of the hippocampal CA1 pyramidal cell layer and dentate gyrus granular cell layer, with neuronal degeneration characterized by cytoplasmic vacuolation and nuclear pyknosis [235]. Transmission electron microscopy shows hippocampal neuronal mitochondria exhibit cristae damage, including cristae fracture, vacuolization, and loss of cristae density. Since cristae are the site of ETC complex assembly, this structural damage reduces Complex IV activity and ATP synthesis. Notably, cristae damage is observed as early as 72 hours post-CTX, preceding neuronal death by 5–7 days, identifying it as an early biomarker of CTX neurotoxicity.

While research directly investigating the precise impact of CTX on core MQC pathways is still limited, the observed mitochondrial functional decline, ROS accumulation, and structural damage strongly imply that MQC systems responsible for clearing damaged mitochondria and maintaining the mitochondrial network’s integrity may be impaired. This likely leads to the accumulation of dysfunctional mitochondria, further exacerbating neuronal injury and subsequent cognitive decline.

Cisplatin

Cisplatin, a first-line platinum-based chemotherapeutic agent, is a significant contributor to CRCI due to its inherent neurotoxicity, with CRCI primarily manifesting as deficits in spatial memory, contextual learning, and executive function [236]. Aberrant neuronal mitochondrial function is widely recognized as a fundamental basis for cisplatin-induced cognitive impairments and associated brain injury [237,238]. In murine models, cisplatin treatment has been shown to impair performance in cognitive tests such as novel object/place recognition and Y-maze tests [4], alongside deficits in contextual fear conditioning and context object discrimination tasks [239].

Direct mitochondrial structural and functional damage

Cisplatin inflicts multi-faceted, irreversible damage to neuronal mitochondria, starting with ultrastructural collapse. Structurally, synaptosomal mitochondria from cisplatin-treated mice reveal mitochondrial swelling, OMM wrinkling, and cristae disorganization or dissolution [4,240,241]. Cristae, critical for ETC complex assembly, are reduced in density, directly compromising OXPHOS efficiency. Functionally, cisplatin significantly inhibits the maximal respiratory capacity (MRC) and spare respiratory capacity (SRC) of synaptosomal mitochondria [64], reduces ATP production, and disrupts mitochondrial membrane potential (ΔΨm) [240], thereby precipitating a bioenergetic crisis in neurons. Cisplatin also induces mitochondrial DNA (mtDNA) damage and suppresses the expression of key mtDNA-encoded subunits of the electron transport chain (e.g., CytB of Complex III, mt-ND1 of Complex I) [242], further compromising mitochondrial respiratory function. Crucially, these damaging effects can be persistent.

Oxidative stress-inflammation feedback loop

Cisplatin triggers a self-amplifying cycle of oxidative stress and neuroinflammation, amplifying mitochondrial damage. Cisplatin promotes increased generation of mitochondrial ROS [243], disrupting cellular redox homeostasis. While cisplatin directly induces ROS, neuroinflammatory pathways can amplify this effect. For instance, cisplatin activates TLR4, which acts via the sphingosine kinase 1/S1P/S1PR1 axis, activates astrocytes, triggering peroxynitrite production. This reactive species can attack and inactivate crucial mitochondrial antioxidant enzymes like MnSOD, further diminishing mitochondrial resilience to oxidative stress and creating a vicious cycle [244]. The sustained oxidative stress and mitochondrial damage activate multiple programmed cell death pathways, including apoptosis, necrosis, pyroptosis, and ferroptosis [239]. Specifically for apoptosis, cisplatin induces the translocation of p53 to mitochondria, promoting cytochrome c release from the mitochondria, activating the downstream caspase cascade, including caspase-9 and caspase-3, ultimately leading to neuronal death [245,246]. Upregulation of miR-429-3p has been associated with reduced mt-ND1 expression and caspase-9 activation [165], suggesting a role for microRNAs in modulating mitochondrial function and apoptosis.

MQC pathway dysregulation

Mitochondrial biogenesis suppression

Cisplatin significantly downregulates PGC-1α, a master regulator of mitochondrial homeostasis and biogenesis. Reduced PGC-1α leads to insufficient generation of new mitochondria, diminishing the neurons’ capacity to replace damaged organelles and enhance resistance to oxidative stress [183]. This deficiency exacerbates neurodegeneration, potentially synergizing with reduced synaptophysin expression and amyloid β/p-Tau deposition [247,248]. However, in neural stem/progenitor cells (NSPCs), low-dose cisplatin might transiently enhance mitochondrial function and biomass, suggesting a potential biphasic effect or cell-type/dose-specific mitochondrial adaptation or stress response [249].

Mitochondrial dynamics and transport

Efficient mitochondrial trafficking along neuronal axons and dendrites is critical for function, particularly in energy-demanding synaptic regions. Cisplatin interferes with this transport by suppressing α-tubulin acetylation levels, a key determinant of microtubule stability regulated by factors like HDAC6 [250]. Cisplatin-induced activation of the DLK-JNK/c-Jun pathway also contributes to α-tubulin deacetylation, further impeding mitochondrial transport [251]. This results in inadequate mitochondrial supply to synapses, exacerbating energy metabolic deficits and synaptic dysfunction.

Intercellular and systemic mitochondrial dysregulation

Cisplatin’s impact on mitochondrial health extends beyond neuronal cell-autonomy, involving glial support and systemic signaling. While astrocytes are relatively more resistant to cisplatin toxicity than cortical neurons, cisplatin impacts neuronal calcium dynamics, closely linked to mitochondrial function [252]. Importantly, astrocytes can transfer functional mitochondria to neurons, a mechanism recognized as vital for neuronal protection and repair. This transfer, dependent on proteins like Miro-1, can rescue neuronal mitochondrial function and calcium homeostasis, mitigating cisplatin-induced damage. This represents a potential intercellular MQC support mechanism.

Furthermore, cisplatin-induced mitochondrial dysfunction may not be confined to the nervous system but also signal systemically to mediate chemotherapy side effects. Cisplatin drives elevated circulating levels of growth differentiation factor 15 (GDF15) [253]. GDF15, a key signal of mitochondrial stress, whose increase may reflect cisplatin-induced mitochondrial oxidative damage, reduced ATP production, or UPRmt activation in peripheral tissues such as skeletal muscle, hypothalamus, or adipose tissue. This peripheral mitochondrial stress, signaled via the GDF15/GFRAL pathway, can suppress appetite and reduce exercise tolerance, hinting at potential links between peripheral mitochondrial health and central cognitive dysfunction.

Targeting mitochondrial function or MQC pathways offers promising strategies for intervening in cisplatin-related cognitive impairment. Intranasal administration of specific mitochondrial modulators reversed cisplatin-induced mitochondrial abnormalities, restored synaptosomal membrane integrity, ameliorated white matter damage, and mitigated cognitive deficits. The use of NAD⁺ precursors like nicotinamide mononucleotide has also been shown to prevent cisplatin-induced mitochondrial defects in neurons. Targeting HDAC6 to improve mitochondrial transport and enhancing astrocyte-to-neuron mitochondrial transfer represent highly promising avenues for future intervention.

5-Fluorouracil

5-Fluorouracil (5-FU), a pyrimidine analog and foundational antimetabolite chemotherapeutic agent, induces CRCI in patients with colorectal, breast, or gastrointestinal cancers, primarily manifesting as deficits in spatial memory, cognitive flexibility, and motor-coordinated learning. Specifically, 5-FU-treated rodents exhibit reduced efficiency in tasks such as the nose-poke test, reflecting impairments in cognitive flexibility or motor coordination [254].

At the cellular level, 5-FU inflicts direct damage upon mitochondria within hippocampal dentate gyrus neurons. Morphological analyses reveal significant mitochondrial swelling and fragmentation of the critical cristae. These structural aberrations directly compromise the function of respiratory chain complexes, leading to a marked reduction in the generation of ATP. 5-FU drives mitochondrial fragmentation by downregulating key fusion proteins such as MFN2 and upregulating fission proteins like FIS1, forcibly shifting the balance towards excessive fission and thus disrupting the integrity of the functional mitochondrial network. Concurrently, 5-FU inhibits the expression of PGC-1α, a critical regulator of mitochondrial biogenesis. This suppression not only hinders the generation of new mitochondria but may also impair the renewal and maintenance of existing ones, collectively contributing to an insufficient pool or functional deficit of healthy mitochondria within neurons, which inhibits the activity of the BDNF/Akt/Nrf2 pathway, potentially leading to aberrant dendritic spine morphology or dysregulated pruning in hippocampal neurons. Furthermore, the insufficient ATP supply impairs the ERK/mTOR pathway, subsequently hindering the synthesis and stability of synaptic proteins, such as the postsynaptic density protein 95 (PSD-95), ultimately weakening synaptic strength and function [254,255].

However, it is important to acknowledge complexities regarding the reported effects of 5-FU’s precise mechanisms. For example, some studies have reported no significant impact of 5-FU treatment on mitochondrial complex I activity, nor observed widespread elevation of pro-inflammatory cytokine levels like IL-1α and TNF-α [256,257]. These findings suggest that the specific impact of 5-FU on particular mitochondrial components or inflammatory cascades may depend on the experimental model, dosage, treatment regimen, or evaluation time point.

Vincristine

Vincristine (VCR) is a vinca alkaloid widely used to treat hematological malignancies. Unlike other chemotherapeutics that primarily target mitochondrial structure directly, VCR’s neurotoxicity is centered on axonal mitochondrial homeostasis, leveraging its canonical role as a microtubule disruptor to cripple MQC in axons. Studies reveal that VCR induces aberrant accumulation of axonal mitochondrial ETC components, significantly impairing oxidative phosphorylation function and leading to subsequent critical ATP depletion [258]. This energy metabolic deficit directly compromises ATP-dependent axonal transport and potentially impairs microtubule stability, which in turn leads to dysfunctional mitochondria that generate ROS. Simultaneously, dysfunctional mitochondria generate ROS, activating the SARM1-mediated axonal degeneration pathway. Crucial experimental insight arises from the mitochondrial fission inhibitor Mdivi-1. Despite its known role in inhibiting fission, studies show that Mdivi-1’s neuroprotective effect is mediated by suppressing mitochondrial Complex III electron leakage and reducing ROS generation. This finding suggests that mitochondrial ROS control, rather than simple dynamics balance, may represent a more clinically tractable key node in VCR-induced neurotoxicity.

Temozolomide

Temozolomide (TMZ), a DNA-alkylating imidazotetrazine agent and first-line treatment for glioblastoma and metastatic brain tumors, is increasingly recognized for its association with CRCI. Its unique ability to readily cross the BBB without significant efflux by P-glycoprotein allows it to target not only tumor cells but also non-malignant brain cells (neural stem cells, mature neurons, and glia), with mitochondrial quality control (MQC) disruption as a central neurotoxic mechanism [259,260]. The primary mechanism involves TMZ-mediated alkylation damage to mitochondrial DNA (mtDNA), which inhibits its replication and transcription, leading to cumulative mtDNA lesions. This mtDNA damage, coupled with electron leakage from impaired electron transport chain (ETC) components, substantially elevates ROS levels. Excessive ROS further exacerbates mitochondrial dysfunction by damaging membranes and mtDNA. This sustained oxidative stress triggers the intrinsic mitochondrial apoptotic pathway, increasing Caspase-9 expression and consequent Caspase-3 activation, culminating in cell death or impaired function. This cascade is considered a principal mechanism underpinning TMZ-induced neurotoxicity, contributing to cognitive deficits.

Busulfan

Busulfan (BU) is a bifunctional alkylating agent used in clinical hematopoietic stem cell transplantation conditioning regimens. BU administration induces episodic memory deficits, evidenced by significantly shortened passive avoidance latencies for both short-term and long-term memory, as well as non-spatial memory impairment [261]. A core mechanism underlying BU neurotoxicity is the severe oxidative stress, characterized by elevated MDA levels in brain tissue, GSH depletion, and suppressed activity of antioxidant enzymes like SOD, and catalase (CAT) [262]. This oxidative burden directly targets mitochondria, leading to mitochondrial membrane lipid peroxidation and mtDNA damage. Crucially, the oxidative damage significantly inhibits the activity of mitochondrial electron transport chain Complex II, thereby compromising oxidative phosphorylation function and reducing ATP generation. The resulting ATP deficit directly impairs neuronal synaptic plasticity, a highly energy-dependent process essential for learning and memory.

Mitochondrial-targeted therapeutic strategies for CRCI

Understanding the pivotal role of mitochondrial dysfunction and impaired MQC in CRCI necessitates the development of effective therapeutic strategies specifically targeting these organelles. Given mitochondria's central role in neuronal energy metabolism, calcium homeostasis, redox balance, and stress responses, restoring their optimal function is paramount for mitigating CRCI. Pharmacological interventions aiming to bolster MQC and function represent a promising avenue. Beyond pharmacological approaches, lifestyle modifications and emerging neuromodulation techniques also offer significant potential by influencing mitochondrial health and resilience.

Pharmacological interventions

Pharmacological strategies for CRCI often converge on improving mitochondrial health, either directly by targeting mitochondrial components or indirectly by modulating cellular pathways that regulate MQC. These interventions can be broadly categorized based on their primary mechanisms: modulators of mitochondrial redox homeostasis, regulators of mitochondrial biogenesis and metabolism, specific mitophagy activators, and agents influencing mitochondrial dynamics (Table 2).

Table 2.

Therapeutic strategies targeting mitochondrial quality control and function for chemotherapy-related cognitive impairment.

Category	Intervention (Agent)	Chemotherapeutic Agent(s)	CRCI Phenotype Improvement	Key Mechanism (MQC / Mitochondrial Function)	Regimen
I. Pharmacological Interventions
A. Modulators of Mitochondrial Redox Homeostasis
	1. Mitochondria-Targeted Antioxidants
	Phenyl-2-aminoethyl Selenide	Doxorubicin	Ameliorated synaptic and memory deficits	Mitigated Dox-induced mitochondrial oxidative stress; reduced Akt and ERK phosphorylation.	10 mg/kg; i.v.; 5 weeks.
	C-phycocyanin	Doxorubicin	Mitigated cognitive impairment	Suppressed mitochondrial oxidative stress and neuroinflammation; rescued mitochondrial abnormalities and dendritic spine loss; restored mitochondrial function and morphology.	50 mg/kg; i.p.; 3 weeks.
	Coenzyme Q10	Cyclophosphamide, Doxorubicin, 5-FU, CAF	Improved cognition; enhanced mitochondrial morphology	Enhanced mitochondrial ETC Complexes I, II, and IV activity; reduced lipid peroxidation; increased GSH, SOD, and CAT levels; counteracted pro-inflammatory cytokines.	40 mg/kg; oral; 3 weeks.
	Oroxylum Indicum Extract	Doxorubicin, Cyclophosphamide	Prevented impaired short-term cognitive performance, spatial learning & memory	Counteracted mitochondrial oxidative stress (decreased ROS, lipid peroxides, blocked GSH depletion); significantly increased mitochondrial Complex I and Complex IV activities.	250-500 mg/kg; oral; 4 weeks.
	2-Mercaptoethane Sulfonate Sodium	Doxorubicin	Ameliorated oxidative protein damage; preserved hippocampal phospholipase C activity	Prevented Dox-induced oxidative stress (reduced oxidative protein damage); preserved phospholipase C activity and choline-containing compounds.	60 mg/kg; i.p.; 15 min before DOX as well as 3 h and 6 h after DOX.
	Mesna	Cisplatin	Improved cognitive impairments, anxiety, muscle strength	Alleviated redox imbalance (GSH/GSSG ratio); reduced neuroinflammation (pro-inflammatory cytokines, MMP-2/9 levels); indirect mitochondrial protection.	150 mg/kg; i.p.; 4 weeks.
	Astaxanthin	Doxorubicin	Ameliorated memory impairment, restored hippocampal architecture	Reduced mitochondrial oxidative stress (suppressed ROS/RNS, PGE-2, Nitric oxide); anti-inflammatory; antiapoptotic.	25 mg/kg; oral; 4 weeks.
	Alpha-Lipoic Acid	Doxorubicin	Protected against memory impairment	Activated Nrf2/HO-1 pathway, reducing mitochondrial oxidative stress and inflammation; anti-inflammatory; antiapoptotic.	50, 100, and 200 mg/kg/day; oral; 28 days.
	Quetiapine	Doxorubicin	Reduced neuronal oxidative stress; protected against neuronal apoptosis	Reduced oxidative stress (MDA, elevated GSH); anti-inflammatory (controlled COX-2, NF-κB, TNF-α); antiapoptotic (Bcl-2/Bax/Caspase-3 pathway modulation).	10, 20 mg/kg; oral; 30 days.
	Ergothioneine	Cisplatin	Restored learning and memory deficits	Reduced mitochondrial oxidative stress (prevented brain lipid peroxidation, maintained GSH/GSSG ratio); restored cholinergic function (AChE activity).	2, 8 mg/kg; oral; 58 days.
	N-acetylcysteine	Cisplatin; Doxorubicin + Cyclophosphamide	Prevented cognitive impairments; reversed anxiety-like behavior and spatial cognition	Improved mitochondrial redox balance (restored hippocampal GSH/GSSG ratio, limited ROS production via KYNA modulation); mitigated hippocampal dendritic branching damage and neuronal apoptosis; anti-inflammatory.	300 mg/kg; oral; 8 days.
	Edaravone	Cisplatin	Alleviated neurobehavioral deficits	Activated Nrf2/HO-1 gene expression; inhibited NF-κB activation; reduced oxidative stress and inflammatory mediators.	10 mg/kg; i.p.; 7 weeks.
	PAN-811	Methotrexate, 5-FU, Cisplatin	Suppressed neurotoxicity in primary neurons	Suppressed increased intramitochondrial ROS; neuroprotection without interfering with anticancer activity.	12mg/kg, i.p., 3 times with 10-day intervals, but 10 min following administration of the anticancer drugs.
	Dehydrozingerone	Temozolomide	Improved cognitive impairment, reversed histopathological features	Improved oxidative stress markers; enhanced anticancer potential.	100 mg/kg; oral; 32 days.
	2. Nrf2 Activators
	Compound 1c / Diroximel fumarate (DRF)	Doxorubicin	Reversed deficits in executive function, spatial & working memory	Activated Nrf2 pathway, decreasing hippocampal MDA and protein carbonyl levels; restored microglial morphology (anti-neuroinflammatory).	Compound 1c: 60mg/kg; oral; 4weeks; DRF: 89mg/kg; oral; 4weeks
B. Regulators of Mitochondrial Biogenesis and Metabolism
	1. SIRT1/PGC-1α Activators & Metabolic Modulators
	Berberine	Doxorubicin	Ameliorated cognitive impairment	Activated mitochondrial biogenesis (upregulated PGC-1α, SIRT1); enhanced antioxidant defense (MnSOD); improved synaptic plasticity (CREB, BDNF).	100 mg/kg; oral; 4 weeks.
	Rosuvastatin	Doxorubicin	Attenuated cognitive impairment	Reduced oxidative stress and neuroinflammation; enhanced neuroplasticity (increased ERK1/2, CREB, BDNF); restored brain histopathological structure.	10 mg/kg; oral; 20 days.
	Empagliflozin	Doxorubicin	Dampened oxidative stress and neuroinflammation, enhanced neuroplasticity	Dampened oxidative stress and neuroinflammation; enhanced neuroplasticity; suppressed PI3K/Akt/mTOR/NF-κB/TNF-α signaling, which impacts mitochondrial function and cellular resilience.	10 mg/kg; oral; 28 days.
	6-bromoindirubin-3′-oxime	Cisplatin	Restored mitochondrial biogenesis, neuroprotection	Restored mitochondrial biogenesis (augmented PGC-1α protein, increased mitochondrial number); implicated GSK-3β/PGC1-α axis; anti-apoptotic/anti-oxidative effects.	8.5 μg/kg; i.p.; 2 weeks.
	Amisulpride	5-FU	Abrogated neuroinflammation, apoptosis, β-amyloid accumulation	Enhanced Wnt/GSK-3β/β-catenin signaling and BDNF levels; abrogated neuroinflammation, apoptosis, β-amyloid accumulation; neuroprotection.	5 mg/kg; oral; 19 days.
	Asiatic acid	5-FU	Prevented deficits in spatial working memory, hippocampal cell proliferation	Promoted hippocampal neurogenesis and cell survival; neuroprotection.	30 mg/kg; 20 days.
	Fluoxetine	5-FU, Temozolomide	Improved memory deficits, enhanced neurogenesis	Enhanced neurogenesis and cell proliferation; improved long-term potentiation	10 mg/kg, oral, 40 days; 5 mg/kg, i.p., 3 weeks.
	Ganoderic acid	5-FU	Improved cognitive dysfunction	Improved hippocampal neuronal and mitochondrial structure; activated mitochondrial biogenesis (PGC-1α); modulated mitochondrial dynamics (MFN2, DRP1, FIS1); upregulated neuronal survival/growth proteins (BDNF, Nrf2, mTOR pathways).	50 mg/kg; i.p.; 24 days.
	Melatonin	Doxorubicin; Temozolomide	Mitigated neuronal degeneration and oxidative stress, promoted neurogenesis	Activated Nrf2/p53-SIRT1 signaling pathway; enhanced endogenous antioxidants; promoted neurogenesis; supported mitochondrial health.	40 mg/kg i.p. for 7 days or 8 mg/kg; oral; 14 days.
	L-carnitine/Acetyl-l-Carnitine	Doxorubicin + Cyclophosphamide	Modulated cognitive impairment	Reversed oxidative damage; corrected inflammatory responses (p65 NF-κB, IL-1β, TNF-α); enhanced synaptic plasticity.	150, 300 mg/kg; i.p.; 3 weeks.
	2. BDNF-Enhancing Agents
	Riluzole	Doxorubicin	Reversed decline in cognitive function and neurogenesis	Enhanced BDNF levels in the hippocampus; prevented chemotherapy-induced reductions of newly born, immature neurons; mitigated neuroinflammation.	13 mg/kg; oral; 6 weeks.
	Agomelatine	Cisplatin	Prevented neurotoxicity and cognitive impairments	Elevated hippocampal BDNF levels; reduced neuroinflammation (regulated GSH, MDA, TNF, and IL-6 levels).	20, 40 mg/kg; oral; 4 weeks.
	Calcitriol	Cisplatin	Attenuated behavioral and cognitive impairments	Upregulated BDNF levels.	100 ng/kg; i.p.; 5 weeks.
	l-Dopa	Temozolomide	Prevented recognition memory deficit	Lowered hippocampal TNF-α; preserved BDNF mRNA expression levels.	25, 75 mg/kg; oral; 16 days.
	3. Other Metabolic Regulators
	Pifithrin-μ	Cisplatin	Preserved neuronal mitochondrial function and cognitive function	Inhibited mitochondrial p53 accumulation; counteracted cisplatin-induced decreased spare respiratory capacity and abnormal mitochondrial morphology.	8 mg/kg; i.p.; 20 days.
	Nicotinamide mononucleotide	Cisplatin	Prevented mitochondrial defects in cortical neurons	Restored NAD+ levels; activated SIRT1; preserved oxidative phosphorylation function; improved mitochondrial biogenesis.	250 mg/kg; i.p.; 4 cycles/53 days.
	Sitagliptin and Vildagliptin	Cisplatin	Restored cognitive function, alleviated neurodegeneration	Reduced oxidative stress (TBARS, GSH, CAT); inhibited neuroinflammation; antiapoptotic; boosted hippocampal neurogenesis/survival (BDNF, PCNA) via AMPK/Akt/CREB signaling.	10 mg/kg; oral; 8 or 4 weeks.
C. Mitophagy Modulators
	2-Hydroxypropyl-β-cyclodextrin	Doxorubicin	Increased neuronal survival, decreased p62, lowered lysosomal pH	Activated mitophagy (TFEB activator, enhanced autophagic flux, reduced p62, lowered lysosomal pH); restored impaired neuronal autophagy and peroxisomal homeostasis.	In vitro: concentration not specified; in vitro; dosage, duration not specified.
D. Mitochondrial Dynamics Modulators
	IACS’8287 (DLK inhibitor)	Cisplatin	Prevented peripheral neuropathy and CRCI	Inhibited DLK-JNK/c-Jun pathway; preserved mitochondrial transport and distribution; prevented axonal degeneration.	30 mg/kg; oral; 21 days.
	Mdivi-1 (fission inhibitor) / M1 (fusion promoter)	Doxorubicin	Restored cognitive function	Modulated mitochondrial dynamics (inhibited fission, promoted fusion); attenuated neuroinflammation and oxidative stress; preserved synaptic integrity; mitigated apoptosis/necroptosis.	Mdivi-1 (1.2 mg/kg), M1 (2 mg/kg), or a combined treatment of Mdivi-1 and M1; i.p., 30 days.
E. Multi-Targeted Natural Compounds & Traditional Formulations
	Kai-Xin-San	Doxorubicin	Attenuated cognitive impairment, improved neural degeneration	Reduced neuroinflammation (decreased pro-inflammatory cytokines, increased anti-inflammatory cytokines, inhibited glial activation); reduced oxidative stress (decreased MDA, increased GSH, SOD, CAT, GSH-Px).	1 g/kg; oral; 3 weeks.
	Fangxia-Dihuang Decoction	Doxorubicin	Improved cognitive impairment, ameliorated neurodegeneration	Reduced neuroinflammation (decreased pro-inflammatory cytokines, increased anti-inflammatory cytokines); enhanced antioxidant defense (increased GSH, GSH-PX, SOD, CAT, decreased MDA).	13.65 g/kg; oral; 3 weeks.
	Piperlongumine	Doxorubicin, Cyclophosphamide, Docetaxel	Protected against social memory impairment	Reduced oxidative stress (modulated Nrf2 mRNA expression); improved synaptic plasticity (regulated ERK1/2 signaling pathway).	2 mg/kg; oral; 12 weeks.
	Minocycline	Doxorubicin-Cyclophosphamide	Preserved neurogenesis (doublecortin-positive cells)	Anti-inflammatory, anti-apoptotic, and antioxidant properties; modulated Casp3, bcl-2, p38, cmyc, γh2ax.	9 mg/mL; oral; duration not specified.
	Troxerutin	Doxorubicin + Cyclophosphamide	Neuroprotective effects, improved intestinal integrity	Improved gut-brain axis (reversed chemotherapy-fecal metabolite alterations, improved intestinal integrity); reduced oxidative stress (Nrf2/HO-1) and neuroinflammation (NLRP3/caspase-1/IL-18/IL-1β).	75, 150, and 300 mg/kg; oral, one hour after receiving DOX and CYCLO; three weeks.
	Nanocurcumin	Doxorubicin	Mitigated oxidative stress, impacted cortical dopamine levels	Reduced oxidative stress (lipid peroxidation, nitric oxide, reduced GSH); preserved dopamine levels; downregulated NLRP3, caspase-1, ZO-1, claudin-1, IL-18, IL-1β; regulated Nrf2/HO-1 pathway.	75, 150, 300 mg/kg; oral; 3 weeks.
	Juglanin	Doxorubicin	Protected against cognitive impairment, ameliorated histopathology	Ameliorated oxidative stress and inflammation; attenuated altered brain histopathological architecture, acetylcholinesterase, and caspase 3 activity.	30 mg/kg/day; oral; 4 weeks.
	Thunbergia erecta leaf ethyl acetate fraction	Doxorubicin + Cyclophosphamide	Ameliorated histopathological changes, enhanced memory & learning	Enhanced antioxidant activity (GSH, H2O2, MDA, catalase); reversed inflammatory cytokines via HMGB1/RAGE pathway suppression.	50, 100, and 200 mg/kg; oral; 3 weeks.
	Diadema savignyi extracts	Cisplatin	Improved thermal sensitivity, reduced cerebral cortex degeneration	Reduced oxidative stress (decreased brain NO, MDA, increased GSH, catalase); reduced neuroinflammation (GFAP reactivity); antiapoptotic (increased Bcl2).	50 mg/kg; i.p.; twice weekly for 4 weeks.
	Kolaviron	Busulfan	Abated episodic memory deficit and testicular dysfunction	Inhibited oxidative stress, inflammatory (TNF-α, IL-1β, NF-κβ) and apoptotic pathways; improved cognitive function, normalized neurotransmitter levels.	200 mg/kg; oral; 56 days.
	Panax quinquefolius-based solution (Qiseng®)	5-FU	Prevented fatigue and impact on neurogenesis	Reduced neuroinflammation (regulated gut microbiota, reduced intestinal/systemic inflammation, IL-6, MCP-1); protected neurogenesis.	140 mg/kg; oral; 3 weeks.
	Captopril	Cisplatin	Attenuated neurotoxicity, enhanced cognitive & behavioral performance	Reduced oxidative stress (MDA, catalase) and neuroinflammation (NF-κB, TNF-α, IL-6, GFAP).	25 mg/kg; oral; 3 weeks.
	Naringin	Cisplatin	Abrogated cognitive deficits and cholinergic dysfunction	Reduced oxidative stress and inflammatory signaling; preserved cholinergic function (down-regulated AChE, iNOS).	25, 50, 100 mg/kg; oral; duration not specified.
	Curcumin	Cisplatin	Improved learning and memory	Reduced oxidative stress (MDA levels, increased SOD activity); restored cholinergic function (AChE activity).	300 mg/kg; oral; 5 weeks.
	Vitamin E	Cisplatin	Reversed spatial memory impairment	Reduced oxidative stress (MDA activity, increased thiol and SOD activity).	200 mg/kg; i.p.; 1 week.
	Negative Findings
	Sodium Valproate	Doxorubicin	Worsened cognitive status and brain antioxidant status	Paradoxically worsened cognitive status and brain antioxidant status (HDAC inhibitor).	50 mg/kg, 100 mg/kg, and 200 mg/kg; oral; 50 days.
II. Non-Pharmacological Interventions
A. Lifestyle and Mind-Body Therapies
	Low-intensity treadmill exercise	Doxorubicin	Prevented cognitive impairment	Preserved hippocampal neuroplasticity; improved hippocampal mitochondrial function; potentially stimulated PGC-1α signaling.	30 min once a day, 8 weeks;
	Physical exercise	Methotrexate + 5-FU; Oxaliplatin + 5-FU	Prevented suppression of hippocampal neurogenesis; improved cognition	Preserved hippocampal neurogenesis; improved mitochondrial health (indirectly by boosting cellular resilience and PGC-1α signaling).	4 days a week and consisted of 35-50 minutes a day in the first two weeks and 50-60 in the last two weeks.
	Enriched environments	Methotrexate + 5-FU	Protected against cognitive impairment	Enhanced neuronal differentiation and neurogenesis in the hippocampus; promoted neuronal resilience and MQC.	Standard vs. enriched cages; 3 months.
B. Nutritional Strategies
	Omega-3 Fatty Acids (EPA, DHA)	Doxorubicin + Cyclophosphamide	Attenuated neuroinflammatory/neurodegenerative gene expression changes	Attenuated neuroinflammation; modulated lipid metabolism (plasmalogens, hippocampal lipids); indirect mitochondrial support.	HFn-3 diet (2% kcals EPA+DHA); 7 weeks.
	Choline Supplementation	Cyclophosphamide + Doxorubicin	Attenuated spatial memory deficits	Preserved cholinergic function (high-affinity choline uptake); neuroprotection.	Choline-enriched diet vs. standard diet (0.12% Ch); 71 days.
	Soymetide	Doxorubicin	Lowered senescence markers, promoted neuronal maturation	Reduced senescence (p53, p21, p16); reduced neuroinflammation; promoted neuronal maturation; modulated Wnt/β-catenin pathway.	10, 50, 100 μg/kg; bilateral hippocampal injection; 4 weeks.
	High Fiber Diet	5-FU	Reduced GFAP expression in hippocampus and midbrain	Modulated gut microbiota-gut-brain axis (increased propionate production); reduced neuroinflammation (GFAP expression).	High fiber diet (4.7% crude fiber); 21 days.
	Walnut consumption	Cisplatin	Improved memory and motor abilities	Reduced cisplatin-induced neurotoxicity; general neuroprotection.	6% dietary walnut; 5 weeks.
	Pistachio supplementation	Cisplatin; Vincristine	Attenuated motor and cognitive impairments	Reduced cisplatin/vincristine-induced neurotoxicity; general neuroprotection.	10% pistachio; oral; 5 weeks.

Modulators of mitochondrial redox homeostasis

Chemotherapy-induced oxidative stress, characterized by the excessive production of ROS and reactive nitrogen species (RNS), is a central pathological feature contributing to CRCI. This ROS surge leads to oxidative damage to mtDNA, proteins, and lipids, compromising mitochondrial integrity and function. Strategies targeting redox balance directly mitigate this damage, often acting within or in close proximity to mitochondria.

Mitochondria-targeted antioxidants (MTAs)

Phenyl-2-aminoethyl Selenide (PAESe), an antioxidant drug, previously known to reduce doxorubicin-associated cardiotoxicity, also ameliorates doxorubicin-induced chemobrain. PAESe reduced Akt and ERK phosphorylation and ameliorated synaptic and memory deficits in mice, indicating its broader neuroprotective role against chemotherapy-induced neuronal injury [263]. A potent anti-inflammatory and antioxidant compound, C-phycocyanin mitigated doxorubicin-induced cognitive impairment in mice by suppressing neuroinflammation and oxidative stress. It also rescued mitochondrial abnormalities and dendritic spine loss, suggesting a multi-targeted approach to restore neuronal and synaptic integrity [222]. As an endogenous antioxidant and electron carrier in the ETC, Coenzyme Q10 has demonstrated neuroprotective effects. In a mouse model of chemotherapy (DOX, CTX, 5-FU, CAF) induced chemobrain, CoQ10 treatment significantly improved cognition, reduced lipid peroxidation, increased GSH, SOD, and CAT levels, and counteracted pro-inflammatory cytokines. Crucially, CoQ10 enhanced mitochondrial Complexes I, II, and IV activity and improved mitochondrial morphology, highlighting its direct impact on mitochondrial function [257]. Oroxylum Indicum Extract (OIE) prevented impaired short-term cognitive performance, exploratory behavior, and spatial learning and memory in various behavioral tests. Mechanistically, OIE counteracted chemotherapy-induced oxidative stress by decreasing reactive oxygen species and lipid peroxides, and by blocking glutathione depletion in the brain. Notably, OIE significantly increased the activities of mitochondrial Complex I and Complex IV in the brain, indicating a dual action of potent antioxidant activity and direct enhancement of mitochondrial respiratory function in mitigating CRCI [219].

2-Mercaptoethane Sulfonate Sodium (MESNA) prevents doxorubicin-induced oxidative stress. Studies show that MESNA ameliorated DOX-induced oxidative protein damage in plasma and brain, prevented the reduction of choline-containing compounds, and preserved phospholipase C activity in the hippocampus, thereby mitigating cognitive decline [264,265]. Further studies in cisplatin-induced neurotoxicity showed MESNA improved cognitive impairments, anxiety, muscle strength, and thermal sensitivity, partially alleviating redox imbalance and reducing pro-inflammatory cytokines and matrix metalloproteinases (MMP-2/9) [266]. As a precursor to glutathione, Gamma-Glutamyl Cysteine Ethyl Ester injections led to significantly decreased protein oxidation and lipid peroxidation in the brains of doxorubicin-injected mice, restoring GSH levels and increasing glutathione-S-transferase activity, suggesting a strategy to protect against chemotherapy-induced cognitive dysfunction [267]. Astaxanthin, a naturally occurring carotenoid, significantly protected against DOX-induced memory impairment, restored hippocampal histopathological architecture, and halted oxidative and inflammatory insults, primarily through its antioxidant, anti-inflammatory, and antiapoptotic activities [268]. Alpha-Lipoic Acid, known for its antioxidant, anti-inflammatory, and anti-apoptotic activities, significantly protected against doxorubicin-induced memory impairment by restoring hippocampal antioxidants and reducing oxidative and inflammatory insults via upregulation of Nrf-2/HO-1 levels [269]. Quetiapine alleviated doxorubicin-induced cognitive deficits by reducing MDA and elevating GSH levels, controlling COX-2, NF-κB, and TNF-α, and protecting against neuronal apoptosis via Bcl-2/Bax/Caspase-3 apoptotic modulation [270]. Ergothioneine significantly restored learning and memory deficits in cisplatin-treated mice, preventing brain lipid peroxidation, restoring acetylcholinesterase (AChE) activity, and maintaining the glutathione/glutathione disulfide ratio in brain tissues [271]. As an antioxidant, N-acetylcysteine (NAC) prevented cisplatin-induced cognitive impairments in ovarian cancer rats without decreasing cisplatin’s anticancer efficacy, mitigating hippocampal dendritic branching damage and neuronal apoptosis. It improved redox imbalance and modulated kynurenic acid levels by limiting its non-enzymatic production by ROS [272,273]. Further expanding its utility, NAC also reversed anxiety-like behavior and impaired spatial cognition induced by a combination of DOX and CTX in rats. This protective effect was specifically linked to restoring the hippocampal GSH/glutathione disulfide ratio, further underscoring NAC’s broad efficacy against oxidative stress-mediated cognitive and psychological disorders induced by diverse chemotherapeutic agents [274].

Edaravone, as a potent free radical scavenger, alleviated cisplatin-induced neurobehavioral deficits by up-regulating Nrf2/HO-1 gene expression and preventing NF-κB activation in the hippocampus [275]. PAN-811 suppressed increased intramitochondrial ROS and blocked the neurotoxicity induced by methotrexate, 5-FU, or cisplatin in primary neurons, without interfering with the anticancer activity of these drugs, highlighting its potential as a targeted neuroprotectant [276,277]. Dehydrozingerone protected against temozolomide-induced cognitive impairment, improving oxidative stress markers, reversing histopathological features, and enhancing temozolomide’s anticancer potential [278].

Nrf2 activators

Nrf2 is a master regulator of endogenous antioxidant responses. Activation of Nrf2 has shown significant therapeutic potential in CRCI. Compound 1c, a prodrug that locally releases the Nrf2 activator monomethyl fumarate (MMF) at sites of oxidative stress, and diroximel fumarate (DRF), which systemically releases MMF, both reversed DOX-induced deficits in executive function, spatial memory, and working memory in mice. These Nrf2 activators decreased MDA and protein carbonyl levels in the hippocampus and restored microglial morphology, confirming Nrf2 as a critical therapeutic target for CRCI [279].

Regulators of mitochondrial biogenesis and metabolism

Maintaining adequate mitochondrial mass and bioenergetic capacity is crucial for neuronal function. Therapeutic strategies that enhance mitochondrial biogenesis (the formation of new mitochondria) or optimize metabolic pathways can counteract chemotherapy-induced energy deficits, often by modulating key signaling nodes such as PGC-1α, SIRT1, and BDNF.

SIRT1/PGC-1α activators and metabolic modulators

Berberine ameliorated DOX-induced cognitive impairment by activating the antioxidative defense via upregulating PGC-1α and MnSOD. It also improved synaptic plasticity through cAMP response element-binding protein (CREB) and BDNF, modulated by Sirtuin1 (SIRT1) expression, indicating its role in promoting mitochondrial biogenesis and function [280]. Rosuvastatin, an HMG-CoA reductase inhibitor, attenuated DOX-induced cognitive impairment, oxidative stress, and neuroinflammation. It increased expression levels of extracellular signal-related kinases 1/2 (ERK1/2), CREB, and BDNF, restoring brain histopathological structure and promoting factors critical for neuroplasticity and mitochondrial support [281]. An SGLT-2 inhibitor, empagliflozin, exhibited neuroprotective potential in DOX-induced chemobrain by dampening oxidative stress and neuroinflammation, and enhancing neuroplasticity. It suppressed the PI3K/Akt/mTOR/NF-κB/TNF-α signaling pathway, which has implications for mitochondrial function and cellular resilience [282]. 6-bromoindirubin-3′-oxime (6BIO), a GSK-3β inhibitor, could restore mitochondrial biogenesis by augmenting PGC-1α protein levels and increasing the number of mitochondria in the cerebral cortex and hippocampus, leading to neuroprotection and anti-apoptotic/anti-oxidative effects in a rat model of cisplatin-induced chemobrain [247]. Amisulpride enhanced Wnt/GSK-3β/β-catenin signaling and increased BDNF levels, abrogating 5-FU-induced neuroinflammation, apoptosis, β-amyloid accumulation, and neurodegeneration [283]. Asiatic acid is，a triterpene compound, could prevent deficits in spatial working memory and hippocampal cell proliferation and survival caused by 5-FU chemotherapy, suggesting a role in neurogenesis and neuroprotection [284]. Fluoxetine improved memory deficits, reversed reduction in cell proliferation, and enhanced neurogenesis in models of 5-FU- and temozolomide-induced cognitive impairment, also enhancing LTP [[285], [286], [287]]. Ganoderic acid (GA) is isolated from Ganoderma lucidum. GA improved 5-FU-induced cognitive dysfunction in mice. It ameliorated damage to hippocampal neurons and mitochondrial structure, improved expression of MB markers such as PGC-1α, and modulated mitochondrial dynamics proteins. GA also upregulated neuronal survival and growth-related proteins (BDNF, p-ERK, p-CREB, p-Akt, p-GSK3β, Nrf2, p-mTOR, and p-S6), suggesting a comprehensive protective effect on neuronal mitochondrial health [254].

Melatonin, as a neuroprotective hormone, mitigates DOX-induced neuronal degeneration and oxidative stress. Melatonin upregulated Nrf2 and SIRT1 gene expression, and downregulated p53, contributing to the activation of the Nrf2/p53-SIRT1 signaling pathway and promoting neurogenesis, thereby enhancing endogenous antioxidants and supporting mitochondrial health [226,288,289]. l-carnitine/Acetyl-l-Carnitine (ALCAR) modulated DOX and CTX-induced cognitive impairment by reversing oxidative damage, correcting inflammatory responses, and enhancing synaptic plasticity biomarkers [53].

BDNF-enhancing agents

An FDA-approved medication, riluzole enhanced BDNF levels in the hippocampus, prevented chemotherapy-induced reductions of newly born, immature neurons, and mitigated neuroinflammation in a female mouse model of DOX-induced cognitive decline [290]. A synthetic melatonin analog, agomelatine, prevented cisplatin-induced neurotoxicity and cognitive impairments by elevating hippocampal BDNF levels and reducing neuroinflammation [291,292]. Supplementation with calcitriol attenuated cisplatin-induced behavioral and cognitive impairments by upregulating BDNF in male rats [293]. l-Dopa, as a well-known CNS medicine, prevented temozolomide-induced recognition memory deficit, correlated with lowered hippocampal TNF-α and preserved BDNF mRNA expression levels [294].

Others

As an inhibitor of mitochondrial p53 accumulation, Pifithrin-μ prevented cisplatin-induced CRCI by preserving neuronal mitochondrial function. Mechanistically, it counteracted cisplatin-induced decreased spare respiratory capacity and abnormal mitochondrial morphology in brain synaptosomes, without compromising the anticancer efficacy of cisplatin [4]. Nicotinamide mononucleotide, a potent NAD⁺ precursor, effectively prevents cisplatin-induced mitochondrial defects in cortical neurons by restoring NAD⁺ levels, activating SIRT1, and preserving oxidative phosphorylation function [295].

Sitagliptin and Vildagliptin are dipeptidyl peptidase-4 inhibitors, and both of them have shown neuroprotective effects. Vildagliptin restored cognitive function, alleviated neurodegeneration, diminished oxidative stress, repressed neuronal apoptosis, inhibited neuroinflammation, and boosted hippocampal neurogenesis/survival by upregulating BDNF and PCNA, mediated by the activation of AMPK/Akt/CREB signaling cascades in cisplatin-induced chemobrain [296]. Sitagliptin also improved locomotor and rotarod activities and restored antioxidant enzymes in cisplatin-treated rats, suggesting neuroprotection against mitochondrial toxicity [297].

Mitophagy modulators

Mitophagy, the selective degradation of damaged mitochondria, is a crucial MQC mechanism. Enhancing the efficient clearance of dysfunctional organelles is paramount for maintaining neuronal health and preventing cognitive decline. DOX can impair neuronal autophagy and lead to accumulation of damaged mitochondria and lipid droplets. Overexpression of Transcription Factor EB (TFEB), a master regulator of the autophagy-lysosome axis, increased the survival rate of DOX-treated neurons. 2-Hydroxypropyl-β-cyclodextrin, an activator of TFEB, also promoted neuronal survival, decreased the levels of p62 (an autophagy substrate, indicating enhanced clearance), and lowered lysosomal pH, demonstrating its potential to restore impaired neuronal autophagy and peroxisomal homeostasis caused by doxorubicin [298,299].

Mitochondrial dynamics modulators

Maintaining a healthy balance between mitochondrial fusion and fission, along with efficient transport, is critical for neuronal integrity and synaptic function. The dual leucine zipper kinase (DLK) is a key mediator of axonal degeneration. A novel brain-penetrant DLK inhibitor, IACS’8287, prevented chemotherapy-induced peripheral neuropathy and CRCI, and preserved mitochondrial function in dorsal root ganglion neurons and brain synaptosomes in mice without interfering with cisplatin’s antitumor activity [251]. This highlights the importance of maintaining axonal mitochondrial transport and distribution. Beyond its effects on biogenesis, GA also modulated mitochondrial dynamics proteins (MFN2, DRP1, and FIS1), preventing excessive fragmentation and supporting a healthy mitochondrial network in 5-FU-induced cognitive dysfunction [254]. A recent study provided compelling evidence that direct modulation of mitochondrial dynamics offers a potent therapeutic strategy against DOX-induced chemobrain. Pharmacological intervention with a potent mitochondrial fission inhibitor (Mdivi-1) and/or a mitochondrial fusion promoter (M1) successfully restored cognitive function in DOX-treated rats. This restoration was accompanied by the suppression of mitochondrial fission in the hippocampus and a concomitant improvement in brain homeostasis. Mechanistically, these mitochondrial dynamic modulators attenuated neuroinflammation, decreased oxidative stress, preserved synaptic integrity, reduced potential Alzheimer’s disease-related lesions, and mitigated both apoptosis and necroptosis following DOX administration. These findings underscore that targeting mitochondrial dynamics, specifically by inhibiting fission and promoting fusion, can protect against DOX-induced cognitive impairment by rebalancing mitochondrial homeostasis and attenuating both oxidative and inflammatory insults [56].

Multi-targeted natural compounds and traditional formulations

Several complex natural compounds and traditional Chinese medicine (TCM) formulations offer multi-targeted neuroprotective effects, often involving antioxidant and anti-inflammatory properties that indirectly support mitochondrial quality control, alongside other benefits.

Kai-Xin-San (KXS) is a TCM formula, which attenuated DOX-induced cognitive impairment in breast cancer mice. KXS protected against neuroinflammation (decreasing pro-inflammatory cytokines, increasing anti-inflammatory cytokines, inhibiting astrocytic hyperplasia and microglial polarization) and reduced oxidative stress (decreasing MDA, increasing GSH, SOD, CAT, GSH-Px), ultimately improving neural degeneration. These broad effects contribute to overall neuronal health and resilience [300,301]. Similar to KXS, Fangxia-Dihuang Decoction (FXDH) significantly improved DOX-induced cognitive impairment in breast cancer animal models. It reduced pro-inflammatory cytokines, increased anti-inflammatory cytokines, enhanced antioxidant enzyme levels (GSH, GSH-PX, SOD, CAT), and decreased MDA. FXDH also ameliorated neurodegenerative lesions and neuroinflammatory responses in the hippocampus, supporting mitochondrial function indirectly [302].

Piperlongumine, an alkaloid known for its anti-inflammatory and antioxidant effects, protected against social memory impairment in mice treated with a doxorubicin, cyclophosphamide, and docetaxel regimen. Its multifactorial mechanisms involved oxidative stress and synaptic plasticity, indicating its role in preserving neuronal function [303]. Minocycline, known for its anti-inflammatory, anti-apoptotic, and antioxidant properties, prevented the reduction in doublecortin-positive neural progenitor cells in chemotherapy-treated mice without diminishing the anticancer efficacy of DOX and CTX in triple-negative breast cancer models, suggesting its utility in preserving neurogenesis [304].

Troxerutin is a rutin derivative showing neuroprotective effects against DOX and CTX-induced chemobrain by reversing chemotherapy-fecal metabolite alterations, improving intestinal integrity, and hindering LPS-induced oxidative damage and neuroinflammation. It demonstrated antioxidant effects via Nrf2/HO-1 and opposed inflammation via NLRP3/caspase-1/IL-18/IL-1β [305]. Nanocurcumin mitigated DOX-induced oxidative stress in rat brain, impacting cortical dopamine levels, lipid peroxidation, nitric oxide, and reduced glutathione [306]. Juglanin, a flavonoid, protected against doxorubicin-induced cognitive impairment by ameliorating oxidative stress and inflammation, and attenuating altered brain histopathological architecture, acetylcholinesterase, and caspase 3 activity [307]. Thunbergia erecta leaf ethyl acetate fraction ameliorated DOX and CTX-induced histopathological changes, enhanced memory and learning, demonstrated pronounced antioxidant activity (GSH, H₂O₂, MDA, catalase), and reversed inflammatory cytokines via HMGB1/RAGE pathway suppression [308].

Extracts from Diadema savignyi significantly improved thermal sensitivity, reduced liver enzymes, decreased brain NO and MDA, and increased GSH and catalase activity in cisplatin-treated rats. Histological and immunohistochemical examinations revealed the extracts reversed cerebral cortex degeneration, reduced GFAP reactivity, and increased Bcl2, demonstrating strong neuroprotective activity [309]. Kolaviron, as a neuro-active extract rich in flavonoids, reversed BU-induced oxidative damage, inflammatory proteins (TNF-α, IL-1β, NF-κβ), and apoptosis in rat brains and testes. It improved cognitive function, normalized neurotransmitter levels, and increased testicular androgenic hormones [261,262].

Panax quinquefolius-based solution (Qiseng®) is a solution containing Panax quinquefolius and vitamin C prevented chemotherapy-induced fatigue and impact on neurogenesis, reduced neuroinflammation, and regulated gut microbiota composition, protecting against intestinal and systemic inflammation in 5-FU-treated mice [310]. Captopril, as an angiotensin-converting enzyme inhibitor, attenuated cisplatin-induced neurotoxicity by reducing oxidative stress (MDA, catalase) and neuroinflammation (NF-κB, TNF-α, IL-6, GFAP), thereby enhancing cognitive and behavioral performance [311]. Naringin is a plant-derived flavonoid, which abrogated cisplatin-induced cognitive deficits and cholinergic dysfunction by down-regulating AChE expression and iNOS signaling pathways, and by preventing oxidative stress-mediated inflammatory signaling [312]. Curcumin improved learning and memory in rats treated with cisplatin, significantly reducing MDA levels and increasing SOD and AChE activities, suggesting restored cholinergic function and enhanced oxidative status [313]. Pre-treatment with vitamin E significantly reversed cisplatin-induced spatial memory impairment and decreased MDA activity while increasing thiol and SOD activity in the hippocampus [314]. While histone deacetylase (HDAC) inhibitors have been explored for neuroprotective potential, sodium valproate (a known HDAC inhibitor) paradoxically worsened cognitive status and brain antioxidant status in DOX-treated animals, highlighting the complexity and context-dependency of neurological pathways [315].

Non-pharmacological interventions

Beyond pharmacological strategies, lifestyle modifications and emerging neuromodulation techniques provide crucial support for brain health, often by bolstering intrinsic MQC mechanisms and overall neuronal resilience.

Lifestyle and mind-body therapies

Regular physical activity is a powerful modulator of brain health and mitochondrial function. Low-intensity treadmill exercise in rats prevented doxorubicin-induced cognitive impairment, preserved hippocampal neuroplasticity, and improved hippocampal mitochondrial function [218]. This highlights exercise as a viable intervention to maintain mitochondrial integrity and cognitive function during or after chemotherapy. Similarly, physical exercise prevented suppression of hippocampal neurogenesis and reduced cognitive impairment in chemotherapy (methotrexate and 5-FU)-treated rats [316]. In mice treated with 5-FU and oxaliplatin, wheel running after chemotherapy improved cognition [317]. Housing rats in enriched environments with social interaction and stimulation protected against chemotherapy (methotrexate + 5-FU)-induced cognitive impairment, including deficits in spatial memory and rule learning. This protection correlated with enhanced neuronal differentiation and neurogenesis in the hippocampus, suggesting that stimulating environments promote neuronal resilience and MQC [318].

Nutritional strategies

Targeted nutritional interventions can provide essential substrates and modulators to support MQC and counteract chemotherapy-induced neurotoxicity.

Omega-3 fatty acids

Dietary enrichment with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) attenuated neuroinflammatory and neurodegenerative gene expression changes in the brains of chemotherapy-treated mice [319]. Omega-3 supplementation also helped maintain levels of plasmalogens and altered hippocampal lipids, which are often associated with cognitive impairment models [320]. However, one study noted no rescue of long-term cognitive deficits from omega-3 supplementation in a long-term CRCI model [321], highlighting the need for further investigation into optimal timing and dosage. Combined with low sucrose, EPA+DHA also influenced insulin resistance and affective side effects during chemotherapy [322].

Choline supplementation

Increasing dietary choline attenuated spatial memory deficits induced by cyclophosphamide and doxorubicin in mice [323]. A choline-enriched diet also mitigated the reduction of high-affinity choline uptake and spatial memory deficits in tumor-bearing mice administered doxorubicin and cyclophosphamide, suggesting a protective role against disruptions in cholinergic function [206].

Soymetide

Soymetide, a thirteen-amino-acid soy-derived peptide lowered senescence markers (p53, p21, p16), pro-inflammatory cytokines, and enhanced the mature neuronal marker NeuN in the hippocampus of doxorubicin-induced senescence mice. Soymetide also modulated the Wnt/β-catenin pathway, suggesting its anti-senescent and neuroprotective potential against cognitive decline [324].

High-fiber diet

A high-fiber diet significantly altered gut microbiota composition and increased propionate production in mice. In the context of 5-FU chemotherapy, this diet reduced GFAP expression (a marker for astrocyte density) in the hippocampus and midbrain, and these effects correlated with propionate concentrations [325]. This indicates that a fiber-rich diet can attenuate chemotherapy-related neuroinflammation via the microbiota-gut-brain axis.

Dietary nuts

Dietary walnut consumption improved memory and motor abilities in cisplatin-treated rats, reversing some of the effects on nociception [326]. Similarly, pistachio supplementation attenuated motor and cognitive impairments induced by cisplatin or vincristine in rats [327].

Discussion and perspectives

CRCI remains a pressing survivorship challenge, affecting a substantial proportion of cancer patients and impairing long-term quality of life. The present synthesis underscores that MQC disruption represents a convergent mechanistic axis linking diverse chemotherapeutic agents to neuronal injury [328]. By integrating evidence from neuroinflammation, BBB compromise, neuronal DNA/protein damage, and advanced neuroimaging, a coherent pathophysiological narrative emerges: chemotherapy-induced mitochondrial dysfunction simultaneously undermines neuronal energy metabolism, perturbs redox balance, derails synaptic maintenance, and amplifies neuroimmune crosstalk.

The review highlights how deficits across all arms of MQC, including mitochondrial biogenesis, mitophagy, dynamics, proteostasis, and mitochondrial-derived vesicle formation, are induced by various chemotherapeutics, albeit through agent-specific mechanisms. Anthracyclines perturb mtDNA integrity and respiratory chain activity while inducing maladaptive dynamics and incomplete mitophagy [329]; alkylating agents prominently trigger oxidative damage and antioxidant inactivation [330]; platinum compounds impair biogenesis and mitochondrial transport [331]; antimetabolites bias fusion–fission balance, while microtubule-targeting drugs exert unique axonal MQC deficits. Despite these variations, the downstream phenotype converges on persistent bioenergetic failure, ROS overproduction, and aberrant organelle turnover.

MQC dysregulation in CRCI shares mechanistic frameworks with neurodegenerative disorders, including the PGC-1α/NRF1/TFAM axis in Alzheimer’s disease [332], PINK1/Parkin-dependent mitophagy in Parkinson’s disease and cristae remodeling defects in amyotrophic lateral sclerosis. This convergence raises two therapeutic implications: (i) CRCI models could leverage the rich preclinical pipeline of MQC-targeted agents under development for primary neurodegeneration; (ii) conversely, CRCI offers a distinct reversible injury model in which MQC restoration may yield faster and more measurable functional recovery.

Despite expanding preclinical evidence, several translational bottlenecks remain. CRCI manifests variably across agents, regimens, and patient susceptibility factors (sex, age, genetic background, comorbidities) [333,334], complicating trial design. MQC disruption may precede overt cognitive decline; current human studies often capture late-stage phenotypes, missing the therapeutic window [335]. There is a lack of validated, clinically accessible biomarkers for mitochondrial injury in CRCI. Peripheral indices (circulating mtDNA, GDF15, mitochondrial content in PBMCs) and neuroimaging-derived metabolic metrics require systematic validation for clinical application [335,336]. Many mitochondria-targeted small molecules or peptides face poor brain penetration; strategies such as nanoparticle carriers, intranasal formulations, or mitochondrial transplantation require rigorous safety and pharmacokinetic studies [337]. These gaps underscore the need for cross-disciplinary approaches integrating oncology, neurology, and mitochondrial biology.

The therapeutic landscape mapped herein spans pharmacological, physical, nutritional, and psychological domains. Mitochondria-targeted antioxidants directly counteract intramitochondrial ROS; metabolism regulators stabilize electron transport and ATP generation; biogenesis activators expand functional mitochondrial mass; mitophagy enhancers selectively remove irreparable organelles. Non-pharmacological interventions, including structured exercise, mind-body therapies, and targeted nutrition, offer complementary benefits by stimulating PGC-1α signaling, attenuating neuroinflammation, and improving systemic metabolic resilience.

Emerging interventions are frontier strategies with high translational potential but are currently limited to proof-of-concept models. Preclinical data suggest that multi-target MQC modulation, combining antioxidant, biogenesis-promoting, and mitophagy-enhancing actions [338,339], may be superior to single-pathway intervention, reflecting the interconnectedness of MQC subsystems. Agent-specific MQC fingerprints should be mapped in human cohorts using multi-omics, advanced imaging, and functional assays to guide tailored interventions [340]. MQC biomarkers should be incorporated as inclusion criteria and surrogate endpoints, enabling early-phase studies to test target engagement before large-scale cognitive outcome trials. Evaluate synergistic regimens that integrate MQC-targeted nutraceuticals/pharmacologics with neurorehabilitation, exercise, or neuromodulation, aiming for additive mitochondrial, vascular, and synaptic benefits.

The cumulative evidence positions MQC failure as a primary mechanistic driver and tractable therapeutic pathway in CRCI. Given the organelle’s centrality in neuronal metabolism, redox balance, and survival signaling, restoring MQC integrity addresses both upstream cytotoxic triggers and downstream synaptic failure. The next phase of CRCI research should transition from descriptive pathology to precision targeting, leveraging MQC as both a biomarker platform and an intervention point. Such a paradigm holds promise not only for mitigating chemobrain but also for informing the development of forganelle-centered therapies across a spectrum of CNS injuries.

CRediT authorship contribution statement

Jie Chen: Investigation, Writing – original draft. Xinyu Chu: Visualization, Writing – original draft. Yue Wu: Resources, Visualization. Li Su: Data curation, Investigation. Mingqi Wang: Investigation. Xuemei Zhao: Data curation, Investigation. Xiaohong Wei: Supervision. Guiyang Xia: Supervision. Huan Xia: Supervision. Sheng Lin: Conceptualization, Funding acquisition, Investigation. Mei Zhang: Conceptualization, Funding acquisition.

Declaration of competing interest

This study was supported by the Collaborative Innovation Project of Universities in Anhui Province (GXXT-2023-078), the Research Project on Integrated Traditional Chinese and Western Medicine for Chronic Disease Management (CXZH2024157), the State Key Program of National Natural Science of China (Grant No.82430116), the Special Fund of Central Committee High Level Chinese Medicine Hospital (CZ015-DZMG-LJRC-0014). There are no conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. we would like to declare on behalf of our co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. All the authors listed have approved the manuscript that is enclosed.