Mitochondrial dynamics and cancer: mechanisms and targeted therapy

Abstract

Mitochondria, as key organelles in eukaryotic cells, regulate cellular energy homeostasis and functional integrity through dynamic processes, including fission, fusion, autophagy, and transport, underpinned by precise molecular mechanisms. In healthy cells, the equilibrium of mitochondrial dynamics ensures network quality control and metabolic coordination. In contrast, cancer cells exhibit multi-dimensional dysregulation characterized by hyperactive fission, impaired fusion, and compensatory upregulation of respiratory chain assembly factors, creating a state of “morphology-function decoupling”. These alterations drive tumor progression by reprogramming cellular metabolism, promoting proliferation, inhibiting apoptosis, enhancing migration and drug resistance, and facilitating immune evasion. This review elucidates the molecular mechanisms underlying mitochondrial dynamics, their dysregulation in cancer, and their influence on tumor behavior, while also addressing the core challenges of current targeted therapeutic strategies and the novel therapeutic paradigm of “network remodeling”, offering new insights into tumor biology and precision cancer therapy.

Graphical Abstract

Introduction

Mitochondria are highly structured organelles with diverse functions in eukaryotic cells. Their unique double-membrane architecture—comprising the outer mitochondrial membrane (OMM), inner mitochondrial membrane (IMM), intermembrane space (IMS), and the mitochondrial matrix enclosed by the inner membrane—forms the basis for their complex physiological roles (Nunnari and Suomalainen 2012). This structure is dynamic and highly adaptable, capable of adjusting its morphology and distribution in response to the cell’s metabolic demands, environmental stimuli, or physiological state. In high-energy-demand cells (e.g., cardiomyocytes), mitochondria often form an elongated tubular network, optimizing energy transfer through extensive membrane connections. Under stress, they can fragment to meet local energy needs or clear damaged components (Giacomello et al. 2020). As the “powerhouses” of eukaryotic cells, mitochondria generate adenosine triphosphate (ATP) via oxidative phosphorylation (OXPHOS) and are involved in critical processes such as cell proliferation, differentiation, innate immune regulation, metabolism, calcium homeostasis, redox balance, signal transduction, and apoptosis (Dache And Thierry 2023; Kiriyama and Nochi 2017; Mookerjee et al. 2015). Dysfunctional mitochondria contribute to metabolic and neurodegenerative diseases and play a pivotal role in cancer development, offering valuable targets for diagnosis and treatment (Lightowlers et al. 2015; Mishra et al. 2014; Suomalainen And Battersby 2018).

Recently, mitochondrial dynamics—the processes governing changes in mitochondrial morphology, quantity, and location—has become a central focus of cancer research (Ishihara et al. 2015). In normal cells, mitochondria undergo fission to segregate damaged fragments and fusion to restore genetic material and functional proteins, maintaining mitochondrial network homeostasis. In cancer, this balance is disrupted: most tumor cells exhibit excessive fission and reduced fusion, leading to a fragmented mitochondrial network. These abnormalities not only alter tumor cell metabolism (e.g., the Warburg effect) but also enhance tumor progression by modulating processes such as proliferation, apoptosis, migration, and immune evasion (Arismendi-Morillo 2009; Inoue-Yamauchi and Oda 2012; Srinivasan et al. 2017). Of note, this dynamic imbalance is highly context-dependent: in most solid tumors, hyperactivation of Drp1-mediated fission promotes malignant progression; whereas in specific tumors (e.g., pancreatic cancer) or under drug-resistant conditions, enhanced fusion instead confers a survival advantage, highlighting unresolved controversies in the field (Boulton And Caino 2022). This complexity suggests that mitochondrial dynamics is a critical source of tumor heterogeneity and a potential target for precise therapeutic intervention.

However, the therapeutic translation targeting mitochondrial dynamics faces core challenges: most existing strategies focus on a single molecule (e.g., Drp1 inhibitors) and ignore the systematic coupling of multi-dimensional processes including fission, fusion, autophagy and transport. Meanwhile, the distinct demands for mitochondrial dynamics between tumors and normal tissues (such as myocardium and neurons) have not been fully exploited (Jin et al. 2022; Zhang et al. 2025). Therefore, an in-depth understanding of the translational logic of mitochondrial dynamics from molecular mechanisms to tumor abnormalities, and the construction of a novel therapeutic paradigm centered on “network remodeling” rather than “single-point blockade”, represent the key to breaking through the current bottleneck.

Grounded in a multi-dimensional regulatory framework of mitochondrial dynamics, this review systematically explicates: (1) the molecular mechanisms of the fission–fusion axis, quality control systems, and spatial transport, their systematic imbalance in cancer, and how respiratory chain assembly achieves metabolic compensation; (2) the mechanisms by which dynamic dysregulation drives malignant phenotypes; and (3) targeting strategies directed at dynamic networks and their translational challenges. This work aims to establish theoretical underpinnings and strategic directions for optimizing precision cancer therapy approaches based on mitochondrial dynamics.

Mitochondrial dynamics: From molecular mechanisms to tumor aberrations

Mitochondria undergo continuous dynamic changes within cells, involving cycles of fission, fusion, mitophagy, and transport (Fig. 1). Each stage is tightly regulated by a complex network of key proteins (e.g., Drp1, MFN, PINK1) and upstream signaling pathways (e.g., AMPK, mTOR) that respond to cellular metabolic demands and environmental changes (Fig. 2).These processes govern mitochondrial morphology, quality, quantity, distribution, and function within cells (Chen et al. 2023). Under physiological conditions, fission and fusion maintain the topological balance of the network, autophagy eliminates damaged components, and trafficking enables the precise spatial distribution of energy (Adebayo et al. 2021; Joaquim And Escobar-Henriques 2020; Spinelli And Haigis 2018). Maintaining this balance is crucial for mitochondrial efficiency and cell fate determination (Tilokani et al. 2018). However, under the selective pressure of the tumor microenvironment (TME), this balance undergoes a systematic shift toward “hyperfission, fusion inhibition, autophagic dysregulation, and enhanced directed trafficking”, leading to the formation of a “fragmented network” that sustains the malignant phenotype. In this section, we juxtapose the molecular mechanisms of mitochondrial dynamics with tumor aberrations for integrated analysis to elucidate how such dynamic imbalance acts as a core driver of tumor metabolic adaptation and progression.

Fig. 1.

Schematic diagram of mitochondrial dynamics. A Mitochondrial fission and fusion processes. The primary fission factor is Drp1. The fusion process is divided into outer membrane (OMM) fusion and inner membrane (IMM) fusion: outer membrane fusion is mainly mediated by MFN1 and MFN2, while inner membrane fusion is primarily mediated by Opa1. B Mitophagy: The PINK/Parkin complex targets damaged mitochondria and transports them to lysosomes for degradation. C Mitochondrial transport along microtubules is promoted by the TRAK/Miro motor adapter complex. Figure is created by Figdraw.

Adapted from: Chen W, Zhao H, Li Y. Mitochondrial dynamics in health and disease: mechanisms and potential targets. Signal Transduct Target Ther. 2023;8:333. Available under a CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).

Fig. 2.

Key regulatory proteins and signaling pathways involved in mitochondrial fusion and fission. Blue arrows stand for the activation or enhancement of pathways, whereas orange lines represent the inhibition or inactivation of pathways. Figure is created by Figdraw.

Adapted from: Chen W, Zhao H, Li Y. Mitochondrial dynamics in health and disease: mechanisms and potential targets. Signal Transduct Target Ther. 2023;8:333. Available under a CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).

Fission–fusion axis: Bipolar dysregulation of dynamic balance

Molecular mechanisms and physiological significance

Mitochondrial fission generates two daughter mitochondria, which is critical for clearing damaged mitochondria and ensuring proper organelle distribution during cell division (Al Ojaimi et al. 2022; Tábara et al. 2025; Wang et al. 2024). This process is mainly regulated by dynamin-related protein 1 (Drp1, also known as DNM1L), a cytoplasmic GTPase containing a GTPase domain, a middle helical domain, and a GTPase effector domain (Bleazard et al. 1999; Fukuda et al. 2023). Inactive Drp1 exists as monomers; upon activation, it oligomerizes into ring-like structures that encircle mitochondria (Fröhlich et al. 2013; Ingerman et al. 2005; Ji et al. 2015). GTP hydrolysis drives membrane constriction and fission, after which Drp1 dissociates and returns to the cytoplasm for reuse (Cheng et al. 2020). Drp1 localization to the mitochondrial outer membrane is mediated by several receptors, including mitochondrial fission factor (Mff), fission protein 1 (Fis1), and mitochondrial dynamics proteins 49/51 (MiD49/51) (Fonseca et al. 2019; Kamerkar et al. 2025; Losón et al. 2013; Zerihun et al. 2023). Mff is the most critical receptor in mammalian cells, directly binding to Drp1 via its amino terminus, with its overexpression inducing mitochondrial fragmentation (Otera et al. 2010). Fis1 is essential in yeast but functionally controversial in mammals, with minimal effects on mitochondrial morphology after knockout (Tábara et al. 2025; Yoon et al. 2003). MiD49/51 promote fission independently of Fis1 and Mff (Losón et al. 2013; Palmer et al. 2013), while their overexpression sequesters Drp1 to inhibit its function and elongate mitochondria (Palmer et al. 2011; Samangouei et al. 2018).

Drp1 activity is primarily regulated through phosphorylation modifications (Adaniya et al. 2019; Chang And Blackstone 2010). Phosphorylation at Ser616, mediated by kinases including CDK1, PKCδ, ERK1/2, CDK5 and CAMKII (Chang And Blackstone 2010; Zaja et al. 2014), enhances its GTPase activity, promoting mitochondrial localization and fission (Yu et al. 2011). In contrast, phosphorylation at Ser637 inhibits Drp1 activity and prevents fission. Protein kinase A (PKA)-mediated phosphorylation at this site blocks Drp1 translocation to the OMM, while calcineurin promotes mitochondrial cleavage by dephosphorylating Ser637 (Cribbs And Strack 2007). Notably, phosphorylation of Ser637 by kinases CaMK1α and ROCK1 unexpectedly enhances fission activity, indicating that intracellular environments (e.g., kinase spatiotemporal specificity, presence of auxiliary proteins) can significantly alter the functional outcomes of the same modified site (Xu et al. 2016b). In addition to phosphorylation, other post-translational modifications, such as ubiquitination, SUMOylation, and S-nitrosylation, also regulate Drp1 function (Adaniya et al. 2019; Chang And Blackstone 2010; Figueroa-Romero et al. 2009). For instance, MARCH5-mediated ubiquitination degrades Drp1 and MiD49 to suppress fission (Xu et al. 2016a). SUMO1 modification stabilizes Drp1 to promote fission, whereas SENP3-mediated deSUMOylation strengthens Drp1-Mff binding to amplify fission (Guo et al. 2013a). In Alzheimer’s disease, β-amyloid-induced oxidative stress triggers Drp1 S-nitrosylation, causing excessive fission and neuronal damage (Fröhlich et al. 2013). Furthermore, post-translational modifications of Drp1 receptors also modulate fission: AMPK-mediated Mff phosphorylation enhances Drp1 recruitment (Hanada et al. 2024; Steinberg And Hardie 2023; Toyama et al. 2016), while MARCH5-mediated MiD49 ubiquitination and degradation inhibits fission (Shiiba et al. 2020; Xu et al. 2016a). Multiple signaling pathways coordinate mitochondrial fission via these modifications on Drp1 and its receptors.

Mitochondrial fission is non-random and tightly linked to cellular metabolic status, stress signals, and organelle interactions such as with the endoplasmic reticulum (ER) (Tábara et al. 2025). The ER-mitochondria contact sites often act as initiation points for fission. The ER facilitates membrane constriction by recruiting actin-related proteins (e.g., INF2), creating conditions for Drp1 assembly. Fission typically occurs at regions where mitochondrial DNA (mtDNA) is replicated, ensuring that daughter mitochondria inherit complete genetic material. Furthermore, under stress conditions, such as oxidative damage or nutrient deprivation, fission is enhanced to segregate damaged mitochondrial fragments, allowing their subsequent clearance via autophagy (Tábara et al. 2025).

Mitochondrial fusion integrates mtDNA, metabolic enzymes and essential components between mitochondria to sustain network integrity and functional coordination (Gao And Hu 2021). It supports energy substrate distribution in cardiomyocytes, maintains mtDNA stability in long-lived neurons, and alleviates defects caused by mtDNA mutations, thus protecting against neurodegeneration (van Spronsen et al. 2013; Tábara et al. 2024).

Mitochondrial fusion involves two coordinated steps: outer and inner membrane fusion. Outer membrane fusion is mediated by mitofusin 1 (MFN1) and mitofusin 2 (MFN2) (Song et al. 2009), GTPases that drive membrane tethering and fusion via GTP hydrolysis (Cao et al. 2017; Koshiba et al. 2004). Mutations in MFN2 lead to Charcot-Marie-Tooth disease type 2 A (CMT2A) (Rizzo et al. 2023; Zhang et al. 2024). MFN activity is tightly regulated by post-translational modifications. For example, MEK/ERK-mediated phosphorylation inhibits MFN1 (Pyakurel et al. 2015), HDAC6-dependent deacetylation activates it (Lee et al. 2014), while Parkin-driven ubiquitination degrades MFN2 to prevent fusion between healthy and damaged mitochondria (McLelland And Fon 2018). These modifications work in concert, enabling MFNs to adapt their activity in response to cellular metabolic states and stress signals, ensuring mitochondrial fusion occurs as required. Inner membrane fusion is mediated by optic atrophy 1 (OPA1), an IMM GTPase regulated by proteolytic cleavage and membrane potential (Song et al. 2009). It exists as long (L-OPA1) and short (S-OPA1) isoforms that act together to mediate fusion, ensuring matrix content mixing and maintaining cristae structure for OXPHOS efficiency (Anand et al. 2014; Ishihara et al. 2006). For example, in liver cells under starvation, mitochondrial fusion is enhanced, optimizing the integration of metabolic enzymes to improve fatty acid oxidation and provide energy for the cell (Gaucher et al. 2022; Sebastián et al. 2012).

In summary, mitochondrial fission and fusion form a tightly coordinated axis critical for maintaining cellular homeostasis. Fission ensures uniform mitochondrial distribution during cell division and facilitates the autophagic clearance of damaged mitochondria, whereas fusion enables the mitochondrial network to flexibly adapt to metabolic demands, enhance oxidative phosphorylation capacity, and dilute damaged components to reduce oxidative stress (Gao And Hu 2021; Murata et al. 2020). Dysregulation of either process disrupts mitochondrial network integrity and function, contributing to the onset and progression of multiple pathologies including neurodegenerative diseases, Parkinson’s disease, heart failure, and cancer (Adebayo et al. 2021; Rizzo et al. 2023).

Dysregulation in cancer

Mitochondrial fission‑fusion homeostasis is severely dysregulated in cancer, characterized by excessive mitochondrial fission and impaired fusion, which collectively drive malignant progression.

Cancer cells typically exhibit a fragmented mitochondrial phenotype due to hyperactivated fission machinery: the key fission regulator Drp1 is upregulated in numerous cancers, with enhanced phosphorylation at Ser616 mediated by kinases including ERK and CAMKII, promoting its mitochondrial recruitment and accelerating fission (Chen et al. 2023). For example, an increased Drp1/MFN2 ratio in lung cancer cells results in enhanced mitochondrial fragmentation (Fu et al. 2017), while in breast cancer cells, Drp1 facilitates fission through the RhoA/ROCK1 pathway, supporting cell migration (Zhao et al. 2013). Elevated Drp1 expression is positively correlated with tumor size, lymph node metastasis, and poor prognosis. Patients with lung adenocarcinoma exhibiting higher Drp1 levels have shorter survival times (Yu et al. 2019). Moreover, Drp1 receptors such as Mff and Fis1 are also overexpressed in various malignancies, reinforcing aberrant fission and linking to chemoresistance and unfavorable clinical outcomes (Chen et al. 2023; Karimi et al. 2022; Tak et al. 2018; Zhu et al. 2023).

Concurrently, defective fusion disrupts mitochondrial network integrity and functional homeostasis: reduced expression of MFN1/2 in gastric and liver cancer impairs outer mitochondrial membrane fusion, with low MFN1 levels promoting metastasis (Silva Ramos et al. 2019; Zhang et al. 2020). OPA1 undergoes abnormal processing (e.g., excessive cleavage by OMA1) in ovarian and lung cancer, suppressing fusion and OXPHOS efficiency (Chen et al. 2023), while its overexpression in gefitinib‑resistant lung cancer cells sustains mitochondrial oxidative metabolism and supports drug‑resistant cell survival (Noguchi et al. 2023).

Quality control system: Bidirectional dysregulation of mitophagy

Molecular mechanisms

Mitophagy, as a selective autophagic process responsible for mitochondrial quality control, plays a pivotal role in maintaining mitochondrial homeostasis and overall metabolic balance by accurately identifying and eliminating dysfunctional or redundant mitochondria (Vives-Bauza et al. 2010). The molecular mechanisms involved in mitophagy encompass a series of events, including damage sensing, signal transduction, autophagosome targeting and encapsulation, and lysosomal degradation. These processes are primarily regulated through both ubiquitin-dependent and ubiquitin-independent pathways (Lu et al. 2023) (Fig. 3).

Fig. 3.

Mechanisms of mitophagy. The ubiquitin-dependent pathway can be divided into two types: Parkin-dependent and Parkin-independent. When mitochondria are damaged, PINK1 binds to TOM. Subsequently, it recruits Parkin from the cytoplasm, phosphorylates and activates Parkin, and then recruits p62. p62 then binds to LC3 to form autolysosomes, thereby completing mitophagy through the Parkin-dependent pathway. The mechanism of the Parkin-independent pathway is as follows: PINK1 directly phosphorylates ubiquitin, thereby recruiting autophagy receptors containing ubiquitin-binding domains (UBDs) (such as OPTN and NDP52). These autophagy receptors then recruit LC3, ultimately completing mitophagy. Additionally, there is also an ubiquitin-independent pathway: some proteins present in mitochondria (such as NIX, BNIP3, and FUNDC1) can directly bind to LC3 without undergoing ubiquitination, thereby completing mitophagy. Figure is created by Figdraw.

The ubiquitin-dependent pathway is primarily centered on the PINK1/Parkin pathway. PTEN-induced kinase 1 (PINK1), a serine/threonine kinase consisting of 581 amino acid residues, is encoded by the PINK1 gene (Matsuda et al. 2010). Parkin, a cytoplasmic E3 ubiquitin ligase, plays a key role in this pathway (Narendra et al. 2008). Under normal conditions, PINK1 is translocated to the IMM and degraded (Matsuda et al. 2010). However, when mitochondrial damage leads to collapse of the membrane potential (ΔΨm), PINK1 is unable to translocate into the matrix and is instead retained on the OMM. It binds to the outer membrane translocase complex (TOM), undergoes autophosphorylation, and recruits cytoplasmic Parkin. PINK1 subsequently phosphorylates and activates Parkin, which then ubiquitinates OMM proteins (e.g., MFN1/2 and VDAC1), forming a ubiquitinated signaling platform that recruits autophagic adaptor proteins such as p62/SQSTM1 and NDP52 (Nguyen et al. 2016). These adaptors bind to Atg8/LC3 family proteins on the autophagosomal membrane via their LC3-interacting regions (LIR), mediating the targeted connection between mitochondria and phagophores (Lazarou et al. 2015). Additionally, PINK1 directly phosphorylates ubiquitin at Ser65 to form p-Ub, which recruits autophagic receptors containing ubiquitin-binding domains (UBDs) (e.g., Optineurin), enhancing the efficiency of autophagosome recognition of mitochondria via a Parkin-independent pathway (Lazarou et al. 2015).

The ubiquitin-independent pathway involves specific receptors on the mitochondrial membrane that mediate autophagic recognition directly, with notable receptors including NIX/BNIP3, FUNDC1, and Bcl-2L13. These receptors do not require ubiquitination and can be rapidly activated under stress conditions (e.g., hypoxia and oxidative damage), directly linking mitochondria to the autophagosomal membrane to initiate phagophore elongation and closure (Gatica et al. 2018). For instance, under hypoxic conditions, FUNDC1 is activated through Ser13 dephosphorylation (mediated by PGAM5) and Ser17 phosphorylation (mediated by ULK1), and its LIR binds directly to LC3, triggering mitophagy (Chen et al. 2014; Liu et al. 2012).

Ultimately, autophagosomes containing mitochondria fuse with lysosomes to form autolysosomes. The mitochondrial contents (including mtDNA, proteins, and lipids) are degraded by lysosomal acid hydrolases (e.g., cathepsins), and the resulting degradation products (e.g., amino acids, nucleotides) are recycled to meet cellular metabolic needs (Lu et al. 2023). The precise regulation of mitophagy is vital for cellular homeostasis. Dysregulation of this process, such as mutations in PINK1/Parkin or abnormal receptor expression, is associated with various pathological conditions, including neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease), myocardial ischemia–reperfusion injury, and tumor metabolic reprogramming, making mitophagy a promising target for therapeutic interventions (Georgakopoulos et al. 2017).

Bidirectional regulatory dysregulation in cancer

Mitophagy in cancer often exhibits “bidirectional dysregulation”, either being suppressed to accumulate reactive oxygen species (ROS) and promote mutations, or activated to adapt to stress.

In some tumors, defects in the PINK1/Parkin pathway impair mitophagy, leading to the accumulation of damaged mitochondria that release ROS, thereby inducing DNA mutations. For example, Parkin-deficient mice are prone to spontaneous liver tumor formation due to their inability to clear mitochondria with accumulated ROS (Matsuda et al. 2015). Nevertheless, mitophagic defects in cancer can also become a vulnerability of cancer cells. Studies have shown that PINK1 is intrinsically downregulated in gastric adenocarcinoma tissues and AGS cell lines. Moreover, after mitochondrial damage is induced by agents such as indomethacin, cancer cells still fail to effectively upregulate the expression of PINK1 and its downstream key mediator protein Parkin, resulting in impaired initiation of mitophagy. As a consequence, impaired mitochondria cannot be efficiently cleared and thus accumulate continuously, ultimately triggering cell death (Ghosh et al. 2024b).

In hypoxic and nutrient-deficient tumor microenvironments (TMEs), tumor cells enhance mitophagy to provide energy and raw materials. For instance, liver cancer cells upregulate BNIP3 under hypoxia to activate mitophagy, degrade damaged mitochondria, and release metabolites that promote cell survival (Sun et al. 2014). However, excessive mitophagy can also induce cancer cell death. In malignant glioma cells stimulated by ceramide, the upregulation of BNIP3 triggers mitophagy, initiating a death program by enhancing mitochondrial degradation (Dorn 2010; Jawhari et al. 2016). Additionally, when anticancer compounds target tumor cells, they can directly damage mitochondria or induce stress signals such as ROS, which activate mitophagy in a large number of damaged mitochondria, ultimately leading to cell death due to mitochondrial loss (Choubey et al. 2021; Dany et al. 2016; Mazure et al. 2011).

Spatial distribution system: Pathological reprogramming of directed transport

Molecular mechanisms

Directed transport of mitochondria along the cytoskeleton—primarily along microtubules—ensures the precise spatial delivery of energy. This process is mainly mediated by kinesin and dynein (Morin et al. 2022). Kinesin family members, such as KIF5, facilitate anterograde transport by binding to adapter proteins TRAK1/2, directing mitochondria toward the cell periphery. Conversely, the dynein-dynactin complex governs retrograde transport toward the cell center (Morin et al. 2022). These motor proteins interact with mitochondria through adapter proteins on the mitochondrial membrane, such as MIRO, a mitochondrial Rho GTPase (van Spronsen et al. 2013). MIRO senses Ca²⁺ signals to regulate transport: under high Ca²⁺ conditions, MIRO undergoes a conformational change that disrupts the interaction between mitochondria and kinesin, halting transport; in a low Ca²⁺ environment, the complex reassembles, and transport resumes (Macaskill et al. 2009). Disruptions in mitochondrial transport are linked to various pathological conditions, including neurodegenerative diseases and cancer (Morin et al. 2022).

Directional enrichment in cancer

Mitochondrial transport is abnormally activated in tumors, resulting in directional enrichment of mitochondria at energy-demanding sites (e.g., the migration front). In various tumor cells, motor proteins like kinesin transport mitochondria to lamellipodia, providing ATP to support actin cytoskeleton remodeling and enhancing cell migration (Morin et al. 2022; Zampieri et al. 2021; Zhao et al. 2013). For example, fragmented mitochondria accumulate in pseudopodia in breast cancer cells, and their quantity is positively correlated with invasiveness (Zhao et al. 2013). In ovarian cancer cells, the overexpression of Miro, KIF5, and other proteins increases invasiveness and is associated with poor prognosis (Morin et al. 2022). Furthermore, under hypoxia, mitochondrial retrograde transport is enhanced. ROS produced by perinuclear aggregated mitochondria activate the transcription factor HIF1α, which promotes the transcription of cell survival and mitochondrial metabolism-related genes, helping cancer cells adapt to the hypoxic environment (Morin et al. 2022). Additionally, tumor cells can acquire healthy mitochondria from stromal cells in the microenvironment (such as mesenchymal stem cells and cancer-associated fibroblasts) through tunneling nanotubes (TNTs), boosting ATP production and chemoresistance (Zampieri et al. 2021). For instance, breast cancer cells exhibit significantly increased doxorubicin resistance after acquiring mitochondria from endothelial cells (Pasquier et al. 2013). TNT formation depends on actin polymerization and activation of the Akt-mTOR pathway, and TNTs are more abundant in highly invasive tumors (Zampieri et al. 2021).

Respiratory chain assembly: Functional compensation for structural fragmentation

Molecular mechanisms

Mitochondrial dynamics not only regulate mitochondrial network morphology, but also determine energy metabolic efficiency by maintaining the assembly and stability of respiratory chain complexes. OXPHOS relies on the ordered assembly of respiratory chain supercomplexes (respirasomes) on the IMM, a process precisely regulated by specific assembly factors. As key assembly factors for cytochrome c oxidase (complex IV, COX), cytochrome c oxidase assembly factor 1 (COA1) and COX assembly protein 18 (COX18) are respectively involved in modulating the stability and membrane insertion of complex IV, ensuring efficient function of the electron transport chain, providing a structural foundation for OXPHOS (Ghosh et al. 2024c; Goswami et al. 2025).

Compensatory upregulation in cancer

Although the aforementioned imbalance in mitochondrial dynamics drives the network toward a fragmented architecture, tumor cells do not lose their capacity for OXPHOS. Instead, many cancer cells achieve “structure–function decoupling” by upregulating respiratory chain assembly factors, thereby maintaining oxidative metabolic activity. COA1 is abnormally overexpressed in multiple cancer types (e.g., bladder cancer [BLCA], colon adenocarcinoma [COAD], lung adenocarcinoma [LUAD]), which correlates with enhanced OXPHOS activity, poor clinical prognosis, and altered infiltration of fibroblasts and T cells in the tumor microenvironment. This upregulation is interpreted as a compensatory response by tumor cells to maintain bioenergetic efficiency under conditions of mitochondrial dynamic imbalance (fragmentation) (Ghosh et al. 2024c). Similarly, COX18 dysregulation is a common oncogenic event: its high expression drives tumorigenesis via impaired complex IV assembly, and is associated with oncogenic metabolic reprogramming, cancer-associated fibroblast (CAF) infiltration, and therapeutic resistance in breast cancer (BRCA), LUAD, and stomach adenocarcinoma (STAD). Notably, COX18 gene mutations (such as the R251H missense mutation) and promoter methylation modifications exhibit heterogeneous changes across different tumor types, suggesting context-dependent functionality (Goswami et al. 2025). This coupled mechanism of “structural fragmentation-functional compensation” offers a new perspective for understanding tumor metabolic plasticity. Nevertheless, while elevated assembly factors temporarily sustain oxidative phosphorylation, the physical constraints imposed by network fragmentation—including limited metabolite exchange, increased ROS emission, and progressive heteroplasmy of mtDNA—will inevitably drive tumor cells to initiate deeper metabolic reprogramming.

Taken together, these molecular-level dynamic abnormalities—including Drp1/MFN2-mediated membrane remodeling, autophagic dysregulation via the PINK1/Parkin pathway, TRAK/Miro-dependent directional transport, and COA1/COX18-driven assembly compensation—collectively constitute the structural basis for tumor malignant phenotypes through multi-dimensional mechanisms encompassing energy metabolism, mitochondrial quality control, and spatial energy distribution. The following sections will elaborate how these mechanisms translate into specific malignant behaviors, including metabolic reprogramming, apoptosis evasion, metastatic invasion, and immune microenvironment remodeling.

Impact of abnormal mitochondrial dynamics on the biological behaviors of cancer

Promoting tumor cell proliferation and metabolic reprogramming

The rapid proliferation of tumor cells relies on the “organelle distribution” function of mitochondrial fission. Coordination between mitochondrial fission and mitosis ensures the equal distribution of mitochondria to daughter cells (Taguchi et al. 2007). In various cancers, including liver, breast, and lung cancer, increased expression of fission-related proteins and decreased expression of fusion-related proteins have been observed. This alteration in mitochondrial dynamics promotes tumor cell proliferation. Enhancing mitochondrial fusion or inhibiting mitochondrial fission can suppress tumor cell growth. For instance, inhibiting Drp1 or overexpressing MFN2 impairs lung cancer cells' ability to enter the cell cycle and reduces tumor growth (Fu et al. 2017; Rehman et al. 2012). Inhibition of Drp1 induces mitochondrial fusion, increases Cyclin E expression, triggers replication stress, and ultimately leads to G2/M cell cycle arrest (Qian et al. 2012).

Mitochondria, as key organelles orchestrating energy metabolism and metabolic reprogramming, establish intricate and context-dependent connections with cellular metabolic states through dynamic behaviors, rather than a simple linear correlation. A hallmark metabolic alteration in tumor cells is the Warburg effect, where glycolysis is prioritized over OXPHOS, even under aerobic conditions (Koppenol et al. 2011; Menchikov et al. 2023; Papaneophytou 2024). Enhanced mitochondrial fusion promotes more efficient OXPHOS, leading to increased ATP production. In contrast, impaired mitochondrial fusion disrupts mitochondrial membrane potential and reduces OXPHOS, pushing cells toward glycolytic reliance (Chen et al. 2003; Westermann 2012). In cells with knocked-down MFN1 and MFN2, mitochondrial respiratory chain function is compromised, resulting in decreased OXPHOS (Chen et al. 2005). The metabolic shift from OXPHOS to aerobic glycolysis often correlates with mitochondrial fragmentation (Plecitá-Hlavatá et al. 2008). For example, a link between mitochondrial fragmentation and glycolysis has been observed in neuroblastoma and bladder cancer cells (Hagenbuchner et al. 2013; Konstantakou et al. 2015). This fission-mediated glycolytic shift is not merely a passive consequence but involves active signaling crosstalk: Drp1-dependent fragmentation can regulate glycolytic enzyme activity (e.g., PKM2) and lactate production, while also supporting lipid peroxidation and ferroptosis resistance in certain tumor subtypes (Du et al. 2025a). Notably, mitochondrial dynamics also intersect with other metabolic pathways beyond glycolysis and OXPHOS. For example, enhanced fusion supports fatty acid oxidation (FAO) in cancer stem cells, while fission promotes glutaminolysis to replenish tricarboxylic acid (TCA) cycle intermediates under nutrient deprivation (Ahuja And Zaheer 2026).

However, the association between mitochondrial morphology and metabolic reprogramming remains plagued by unresolved controversies and context dependency that cannot be oversimplified. First, the directionality of regulation is bidirectional rather than unidirectional: while mitochondrial dynamics shape metabolic flux, metabolic cues also feedback to modulate fusion/fission machinery. For instance, HIF-1α can upregulate Drp1 to promote fission, while MYC enhances MFN2 expression to support OXPHOS in normoxic conditions (Ahuja And Zaheer 2026; Du et al. 2025a). Second, metabolic heterogeneity across tumor types and even within the same tumor challenges uniform correlations: some tumors (e.g., acute myeloid leukemia) retain OXPHOS dependence despite increased mitochondrial fission, while others (e.g., pancreatic ductal carcinoma) exhibit fragmented mitochondria but rely on both glycolysis and FAO (Di Gregorio et al. 2022). Third, the functional redundancy of mitochondrial dynamic proteins (e.g., OPA1 isoforms) and their non-metabolic roles (e.g., regulating mtDNA stability) complicate the interpretation of causal relationships between morphology and metabolism (Du et al. 2025a). Thus, tumor cells modulate mitochondrial dynamics to tune metabolic plasticity, but the underlying molecular networks—including the involvement of metabolic sensors (e.g., AMPK, SIRT3) and epigenetic regulators (e.g., histone lactylation)—remain incompletely defined, leaving critical gaps in our understanding of how dynamic mitochondrial remodeling precisely coordinates metabolic reprogramming to support rapid proliferation and therapy resistance.

Inhibiting tumor cell apoptosis

Mitochondrial dynamics play a critical role in regulating the apoptotic process of tumor cells by controlling mitochondrial morphology and function. Enhanced mitochondrial fission activates Drp1, which is recruited to the OMM. This process is often linked to the activation of pro-apoptotic proteins Bax and Bak, which induce mitochondrial outer membrane permeabilization (MOMP), release apoptotic factors such as cytochrome c, initiate the caspase cascade, and promote tumor cell apoptosis. Bax and Bak co-localize with Drp1 in the early stages of apoptosis (Karbowski et al. 2004; Karbowski et al. 2002). Knocking down Drp1 in HeLa cells delays cytochrome c release and inhibits apoptosis (Lee et al. 2004), highlighting the importance of mitochondrial fission in cell death.

However, other studies suggest that the relationship between mitochondrial fission and apoptosis is not absolute (Estaquier And Arnoult 2007; Renault et al. 2015; Sheridan et al. 2008). Mitochondrial fission is not always required for MOMP and apoptosis. Even when mitochondria undergo fission, anti-apoptotic Bcl-2 family proteins can inhibit the release of apoptotic markers, suggesting the presence of mechanisms that decouple fission from apoptosis (Sheridan et al. 2008). In liver cancer cells, overexpression of Drp1 or knockdown of MFN1 has been shown to enhance mitochondrial fission and inhibit fusion, promoting autophagy and suppressing mitochondria-dependent apoptosis, which in turn supports liver cancer cell proliferation (Huang et al. 2016). In HepG2 cells, MFN2 overexpression reduces mitochondrial membrane potential, decreases ER Ca²⁺ concentration, and increases intracellular ROS and mitochondrial Ca²⁺, mediating cell apoptosis (Huang et al. 2017). Thus, while enhanced mitochondrial fission can contribute to apoptosis, it does not always promote tumor cell death, and mitochondrial fusion also plays a significant role in regulating apoptosis. In various cancers, the state of enhanced mitochondrial fission coupled with weakened fusion can inhibit tumor cell apoptosis, promoting tumor growth.

Enhancing tumor invasion and metastasis

Mitochondrial fission is closely associated with tumor invasion and metastasis. Increased mitochondrial fragmentation has been observed in highly invasive breast cancer and metastatic liver cancer. Fragmented mitochondria accumulate at migration fronts, such as cell pseudopodia, providing ATP for cytoskeletal remodeling (Zhang et al. 2020; Zhao et al. 2013). In liver cancer cells, mitochondrial fission activates the Ca²⁺/CaMKII/ERK/FAK pathway, promoting dynamic changes in focal adhesions and the formation of lamellipodia, which enhance cell migration (Sun et al. 2018). Genetic reduction or functional inhibition of Drp1 impairs the migratory capacity of thyroid cancer cells(Ferreira-da-Silva et al. 2015). Conversely, enhanced mitochondrial fusion can inhibit metastasis. Overexpression of MFN1/2 significantly reduces tumor invasion and metastasis (Rodrigues And Ferraz 2020; Zhao et al. 2013). MFN1 deficiency disrupts mitochondrial dynamics, triggering the epithelial-mesenchymal transition (EMT) in liver cancer cells, thereby promoting metastasis (Zhang et al. 2020).

Enhancing tumor drug resistance

Mitochondrial dynamics play a complex yet critical role in tumor cell drug resistance, with their pro-resistance effects strictly dependent on tumor type, microenvironmental cues, and chemotherapy drug properties, and mediated by distinct molecular mechanisms. In most contexts, increased mitochondrial fission and weakened fusion enhance chemoresistance, but the opposite pattern prevails in certain tumors—this discrepancy constitutes a key controversy in the field.

In breast cancer, the pro-resistance effect of mitochondrial fission is triggered by the soft extracellular matrix (ECM) microenvironment of metastatic niches (e.g., lung tissue). Specifically, soft ECM induces the formation of peri-mitochondrial F-actin (driven by Spire1C and Arp2/3), which recruits and activates Drp1. This Drp1-dependent fission increases mitochondrial ROS (mtROS) production, which in turn activates the Nrf2-dependent antioxidant transcriptional response to maintain intracellular redox homeostasis. Ultimately, this enhances the cell’s tolerance to oxidative stress and ROS-dependent chemotherapeutic agents (e.g., cisplatin, arsenic trioxide), leading to drug resistance (Romani et al. 2022). Consistent with this mechanism, Drp1 inhibitors (e.g., Mdivi-1) can block mitochondrial fission, reduce mtROS-Nrf2 pathway activation, and restore the sensitivity of drug-resistant breast and non-small cell lung cancer cells to cisplatin (Qian et al. 2014). In hepatocellular carcinoma (HCC), cisplatin resistance is driven by high expression of Mff. Mff overexpression in cisplatin-resistant HCC cells promotes mitochondrial fission, which maintains mitochondrial quality control and metabolic flexibility to support cell survival under chemotherapy stress. Knocking down Mff inhibits mitochondrial fission by reducing mitochondrial-localized Drp1, disrupts redox balance, and upregulates apoptotic signaling (e.g., cleaved Caspase-3/9), thereby increasing HCC cell sensitivity to cisplatin (Li et al. 2022). In contrast, ovarian cancer exhibits the opposite pattern: cisplatin-resistant SKOV3/DDP cells display enhanced mitochondrial fusion and weakened fission, characterized by longer tubular mitochondria, downregulated Drp1, and upregulated MFN2. This fusion-dominant state maintains mitochondrial network integrity, reduces mtROS production, and stabilizes mitochondrial membrane potential, thereby inhibiting the intrinsic apoptotic pathway. Mechanistically, enhanced fusion protects mitochondria from chemotherapy-induced damage, while weakened fission avoids excessive mtROS release, collectively conferring cisplatin resistance. Notably, inhibiting Drp1 or overexpressing MFN2 in cisplatin-sensitive SKOV3 cells further enhances resistance, confirming that fusion dominance is a pro-resistance adaptation in ovarian cancer (Zou et al. 2021).

The core controversy lies in the inconsistent association between mitochondrial dynamics and chemoresistance across tumor types. This may be attributed to tumor-specific metabolic dependencies (e.g., breast cancer relies on antioxidant metabolism to counteract ECM-induced ROS, while ovarian cancer depends on fusion-mediated mitochondrial integrity to avoid apoptosis) and differences in chemotherapy-induced stress types (e.g., ROS-dependent vs. DNA damage-dependent drugs). Whether the “fission/fusion balance” determines resistance, and how microenvironmental cues (e.g., ECM stiffness, hypoxia) fine-tune this balance, remain to be fully elucidated.

Promoting immune evasion

Abnormal mitochondrial dynamics also promote immune evasion by modulating immune cell function and metabolism within the TME. In normal immune responses, appropriate mitochondrial fission enhances T cell function. During effector T cell formation, Drp1 is phosphorylated at Ser616, leading to increased mitochondrial fission and a fragmented morphology. This structure supports the energy demands of effector T cells, aiding their activation and cytokine production (Buck et al. 2016; Park And Pan 2015). However, in the TME, aberrant mitochondrial fission inhibits T cell function. For example, in tumor-infiltrating lymphocytes (TILs), PD-1 signaling downregulates Drp1 phosphorylation at Ser616, resulting in mitochondrial elongation, reduced T cell motility, impaired proliferation, functional exhaustion, and failure to effectively perform immune surveillance (Simula et al. 2022). In hypoxic conditions, exosomal miR-24 secreted by tumor cells inhibits Myc-regulated MFN1 expression, leading to enhanced mitochondrial fission in TILs, exacerbating T cell exhaustion and promoting immune evasion (Liu et al. 2020). Moreover, cancer cells can transfer mitochondria carrying mtDNA mutations to TILs through TNTs and extracellular vesicles (EVs), inducing metabolic paralysis in T cells. This shift from OXPHOS to glycolysis reduces ATP production, increases ROS accumulation, and leads to T cell senescence and functional exhaustion, thereby significantly reducing the response to PD-1 inhibitors and promoting immunotherapy resistance (Du et al. 2025a). Tumor-infiltrating NK cells also participate in immune responses by destroying cancer cells and secreting cytokines (Malmberg et al. 2017). However, in the TME, NK cells continuously activate the HIF-1α/mTOR-Drp1 pathway due to hypoxia, resulting in excessive mitochondrial fission, metabolic abnormalities, reduced cytotoxicity, impaired infiltration capacity, and decreased survival rate (Ghosh et al. 2025). Excessive mitochondrial fission increases caspase 3 levels in NK cells, promoting their apoptosis and allowing tumors to escape immune surveillance (Chen et al. 2025; Li et al. 2024; Zheng et al. 2019). Beyond hypoxic stress, amino acid depletion (including arginine, leucine, and glutamine) in the TME inhibits the mTOR/cMyc pathway, reducing cytokine production and the expression of NK cell activating receptors; meanwhile, immunosuppressive metabolites such as nitric oxide and kynurenine further exacerbate NK cell dysfunction. Restoring mitochondrial dynamic balance (e.g., inhibiting excessive mitochondrial fission) or targeting metabolic abnormalities (such as addressing hypoxia) can reinvigorate NK cell-mediated anti-tumor activity, including triggering autophagic death of tumor cells (Ghosh et al. 2025). In tumor-associated macrophages (TAMs), mitochondrial dynamics remodeling and oxidative metabolism (including OXPHOS and FAO) collectively drive their polarization toward the M2 phenotype, thereby promoting immunosuppression, angiogenesis, and tumor metastasis in the tumor microenvironment. TAMs undergo characteristic metabolic reprogramming, which is specifically manifested by upregulated expression of arginase 1 (ARG1), reduced glycolysis, and mitochondrial transfer to cancer cells. Meanwhile, TAMs engage in cytokine crosstalk with cancer cells and other components of the tumor microenvironment, and amplify pro-tumor signaling to facilitate tumor progression. Herein, mitochondria serve as a central hub mediating bioenergetic metabolism and immunosuppression (Dubey et al. 2023). Similarly, in the TME, the mitochondrial dynamics and immunometabolism of dendritic cells (DCs) undergo significant remodeling, which synergistically regulate and mediate tumor immune escape. Mitochondrial dynamic imbalance (e.g., abnormal expression of MFN2/Opa1 or Drp1) disrupts the mitochondrial homeostasis of DCs and impairs their antigen processing and cross-presentation functions. In contrast, immunometabolic reprogramming (including pathologically enhanced glycolysis, FAO skewed toward a tolerogenic phenotype, glutamine metabolic disorders, and the production of immunosuppressive metabolites such as kynurenine via tryptophan catabolism) further leads to downregulated expression of DC costimulatory molecules (CD80/CD86), reduced secretion of proinflammatory cytokines (IL-12), and increased release of immunosuppressive cytokines (IL-10). These changes collectively result in DC functional defects, failing to effectively activate naive T cells while inducing the enrichment of regulatory T cells (Tregs), which ultimately impairs the anti-tumor immune response and provides a key guarantee for tumor cells to evade immune surveillance. Additionally, the cGAS-STING pathway activated by mitochondrial damage-associated molecular patterns (DAMPs) further regulates DC maturation and naive T cell priming (Ghosh et al. 2024a).

Collectively, abnormal mitochondrial dynamics act as a central orchestrator of tumor immune evasion by disrupting the function and metabolism of diverse TME-resident immune cells (T cells, NK cells, TAMs, DCs). Targeting mitochondrial dynamics or associated metabolic abnormalities emerges as a promising strategy to reinvigorate immune responses, though context-dependency remains (e.g., tumor type, immune cell subset, hypoxia severity), warranting caution in therapeutic intervention.

The abnormalities of mitochondrial dynamics in cancer are summarized in Fig. 4.

Fig. 4.

Mitochondrial dynamics in cancer. In tumor cells, the levels of mitochondrial fission-related proteins increase, while those of fusion-related proteins decrease. Activation of oncogenic factors such as the Ras oncogene or the MAPK signaling pathway can trigger ERK to phosphorylate serine 616 of Drp1, leading to enhanced mitochondrial fission. This abnormality in mitochondrial dynamics promotes tumor cell proliferation and metabolic reprogramming, inhibits apoptosis, facilitates metastasis and invasion, and enhances tumor drug resistance. Additionally, abnormal mitochondrial dynamics can promote immune evasion by regulating immune cell function in the TME. In tumor-infiltrating lymphocytes (TILs), PD-1 signaling downregulates the phosphorylation of Drp1 at serine 616, resulting in mitochondrial elongation, impaired T cell motility, arrested proliferation, and functional exhaustion, which prevents effective immune surveillance. In the hypoxic microenvironment, sustained activation of the mTOR-Drp1 pathway leads to excessive mitochondrial fission in tumor-infiltrating natural killer (NK) cells, promoting their apoptosis and enabling tumors to escape immune surveillance. Figure is created by Figdraw.

Adapted from: Chen W, Zhao H, Li Y. Mitochondrial dynamics in health and disease: mechanisms and potential targets. Signal Transduct Target Ther. 2023;8:333. Available under a CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).

Cancer therapeutic strategies targeting mitochondrial dynamics

Inhibiting mitochondrial fission

A hallmark of many cancers is excessive mitochondrial fragmentation and reduced fusion. To address this, fission inhibitors have been developed to lower Drp1 levels, regulate Drp1 modifications, inhibit mitochondrial fission, and promote mitochondrial fusion. Mdivi-1, a classic Drp1 inhibitor, suppresses the GTPase activity of Drp1 and reduces mitochondrial fragmentation. In breast and lung cancers, Mdivi-1 restores the sensitivity of drug-resistant cells to cisplatin (Qian et al. 2014). In glioblastoma, Mdivi-1 reduces tumor cell migration, invasiveness, and drug resistance (Wang et al. 2023a). Treatment with Mdivi-1 induces a hyperfused mitochondrial network, disrupting the normal assembly of the mitotic spindle, causing aneuploidy, and ultimately leading to tumor cell apoptosis (Wang et al. 2015). In brain tumor-initiating cells, where Drp1 expression is upregulated, Mdivi-1 induces apoptosis and reduces the tumor-forming potential of these cells (Xie et al. 2015). Furthermore, Mdivi-1 enhances the expression of MHC-I in mouse tumor models, boosting immune-mediated killing (Lei et al. 2022).

P110, another Drp1 inhibitor, is a small peptide that blocks the interaction between Fis1 and Drp1, preventing Drp1 recruitment to mitochondria and affecting cell apoptosis and viability. The inhibitory effect of P110 on mitochondrial fission has been demonstrated in neuronal cell models of neurodegenerative diseases (Guo et al. 2013b; Qi et al. 2013). However, additional studies are needed to clarify its potential role in cancer treatment.

Several other small molecules have been identified that reduce mitochondrial fission by inhibiting Drp1 activity. For example, ERK1/2 inhibitors such as SCH772984 decrease the phosphorylation of Drp1 at Ser616, reducing tumor proliferation rates (Chaikuad et al. 2014; Kashatus et al. 2015; Wu et al. 2023). Exenatide, a member of the glucagon-like peptide family, phosphorylates Drp1 at Ser637, disrupting its localization to mitochondria (Torres et al. 2016). These newly discovered molecules have shown potential in preclinical studies, but further research is necessary to evaluate their safety and efficacy in humans. Nevertheless, their discovery opens new possibilities for developing novel cancer therapies targeting mitochondrial fission.

Promoting mitochondrial fusion

While mitochondrial fission inhibitors have been extensively studied, research on compounds targeting mitochondrial fusion proteins remains limited. Currently, known drugs that promote mitochondrial fusion include hydrazone M1 and 15-oxospiramilactone (S3). Hydrazone M1 can restore mitochondrial fusion in mouse embryonic fibroblasts (MEFs) with MFN1/2 gene knockout (Wang et al. 2012). Although its precise mechanism remains unclear, studies suggest that hydrazone M1 not only protects cells from apoptosis but also regulates components of the ATP synthase complex (Maneechote et al. 2019; Wang et al. 2012). S3 promotes the ubiquitination and accumulation of MFN1/2 without causing their degradation by inhibiting the deubiquitinase USP30, thereby enhancing MFN1/2 activity and inducing mitochondrial fusion (Yue et al. 2014). However, the application of hydrazone M1, S3, and other fusion-regulating compounds in tumors requires further exploration.

Regulating mitophagy

Mammalian target of rapamycin complex 1 (mTORC1) plays a critical negative regulatory role in mitophagy. Under normal physiological conditions, mTORC1 activity inhibits the initiation and progression of mitophagy, ensuring that mitochondrial steady-state balance is not disrupted by excessive autophagic activity. This mechanism is vital for maintaining cellular energy metabolism and survival by preventing unnecessary degradation of undamaged or non-renewal mitochondria (Szwed et al. 2021). However, rapamycin can inhibit mTORC1 activity, thereby relieving its suppression of mitophagy and promoting its occurrence. Rapamycin has demonstrated efficacy in kidney and breast cancers (Zou et al. 2020).

In gastric adenocarcinoma cells, there exists synergistic dysregulation of mitochondrial dynamics and mitophagy, characterized by the coexistence of mitophagic defects and dysregulated mitochondrial fission–fusion homeostasis, which further exacerbates the accumulation of damaged mitochondria. This synergistic dysregulation not only results in cancer cells losing their ability to repair mitochondrial damage but also triggers mitochondrial pathology-mediated cell death by activating pro-apoptotic proteins such as Bax, Puma, and Noxa. Furthermore, this process can be further amplified by a sub-lethal dose combination regimen of Drp1 inhibitors (e.g., Mdivi-1) and mitochondrial pathology inducers (e.g., indomethacin), thereby achieving selective killing of cancer cells without significantly impairing the viability of normal gastric epithelial cells (Ghosh et al. 2024b). This highlights the therapeutic vulnerability during stress-induced mitophagy, and compared with broad-spectrum mitophagy inhibitors, the combination regimen offers a low-toxicity therapeutic strategy. In addition, mitophagic dysregulation is closely associated with the malignant phenotypes of cancer cells; combination therapy targeting this aberrant pathway can effectively inhibit the migratory capacity and stemness of gastric adenocarcinoma cells, providing specific targets and novel strategic support for gastric cancer treatment (Ghosh et al. 2024b).

Further studies are needed to identify additional drugs that regulate mitophagy and exert anti-tumor effects.

Combination therapy strategies

Drugs targeting mitochondrial dynamics can be used in combination with chemotherapeutic agents to enhance tumor cell sensitivity to chemotherapy. For example, the combination of Mdivi-1 and cisplatin can overcome drug resistance in lung cancer cells (Qian et al. 2014). These drugs can also be paired with immunotherapies, such as PD-1 inhibitors, to prevent immune evasion and improve immunotherapy efficacy (Wang et al. 2023b). Furthermore, combining with metabolic inhibitors, such as GLUT1 inhibitors, holds potential. Several GLUT1 inhibitors have been developed and validated in disease models, particularly cancer, to inhibit glycolysis (Chen et al. 2022; Wu et al. 2020). The combination of Drp1 inhibitors and GLUT1 inhibitors may synergistically inhibit glycolysis in tumor cells, enhancing the suppression of tumor cell proliferation. However, further research is necessary to explore the feasibility of specific combination therapy strategies.

Translational challenges and limitations

Despite the promising therapeutic strategies outlined above, translating mitochondrial dynamics-targeted therapies into clinical practice remains challenging. Existing frontline inhibitors face notable pharmacological limitations that restrict their translational application.

Drp1-targeting agents exhibit significant off-target effects: Mdivi-1 not only suppresses pathological fission but also inhibits mitochondrial Complex I, induces dose-dependent ROS imbalance, and potentially interferes with physiological fission due to lack of Drp1 specificity, raising neurotoxicity concerns (Marx et al. 2024; Scheffer et al. 2022). Similarly, the peptide inhibitor P110 suffers from a short half-life, carrier-dependent cell membrane penetration, and target compensation risks—Drp1 can mediate fission via alternative receptors such as Mff, potentially circumventing Fis1-targeted inhibition (Whitley et al. 2019).

Fusion-promoting compounds also face hurdles: Hydrazone M1 lacks reliable in vivo validation data, and its mechanism of action remains unclear, with concerns regarding non-specific effects on GTPase-related pathways and potential cardiotoxicity in energy-demanding tissues (Chen et al. 2023). S3 suffers from concentration-dependent mechanism duality: while low doses promote fusion via USP30 inhibition, higher concentrations trigger apoptosis through Wnt pathway suppression, indicating a narrow therapeutic index and potential off-target effects (Wang et al. 2022). Moreover, robust in vivo validation in tumor models remains lacking, and the cell context-dependent functions of USP30 complicate predictable therapeutic outcomes (Du et al. 2025b).

Beyond individual drug limitations, systemic translational barriers persist: tumor heterogeneity (e.g., adaptive metabolic switching to evade targeting), the absence of selective biomarkers for patient stratification, and unresolved controversies regarding the causal relationships in mitochondrial dynamics collectively hinder clinical translation. Addressing these challenges—through development of highly specific small molecules, identification of predictive biomarkers, and rigorous toxicological evaluation—will be essential for advancing these therapies from bench to bedside.

Conclusion and prospect

Mitochondrial dynamics maintains cellular energy homeostasis and quality control through the precise coupling of fission, fusion, autophagy, and transport. This review reveals that tumors do not simply “disrupt” this system; rather, they transform it into an adaptive mechanism supporting malignant phenotypes through a systematic shift toward “hyperactive fission, suppressed fusion, reprogrammed autophagy, and enhanced directional transport”. Overactivation of the Drp1/Mff axis coupled with impaired MFN/OPA1 function constitutes the structural basis of fragmented networks; bidirectional abnormalities in the PINK1/Parkin pathway (basal defects versus stress-induced hyperactivation) balance genomic stability against survival adaptation; spatial redistribution of mitochondria toward the invasive front and immune cells reshapes the metabolic and immune landscape of the tumor microenvironment; while upregulation of respiratory chain assembly factors such as COA1/COX18 maintains OXPHOS efficiency despite structural compromise, creating a state of “morphological fragmentation yet functional hyperactivity” that represents structural–functional decoupling. These findings establish mitochondrial dynamics as a central regulatory node in cancer initiation and progression.

Therapeutic development targeting mitochondrial dynamics currently stands at a critical inflection point of paradigm shift. While first-generation strategies (e.g., Mdivi-1, P110) have achieved proof-of-concept success, they remain constrained by off-target toxicities and pharmacokinetic limitations. Future therapeutic approaches must transition from “single-node blockade” to precision modulation centered on “dynamic network remodeling”: formulating individualized strategies based on tumor-specific dynamic phenotypes; developing biomarker systems for real-time monitoring of dynamic states (e.g., Drp1/MFN2 ratios, mitochondrial network connectivity) to enable precision stratified therapy; establishing organ-specific protective mechanisms to broaden the therapeutic window; and advancing combination therapeutic strategies. The integration of multi-omics technologies, dynamic imaging, and computational modeling to develop next-generation regulatory strategies that precisely correct dynamic imbalances while preserving physiological functions represents the critical pathway toward clinical translation for this field. This endeavor not only deepens our understanding of tumor biology but also marks a significant stride into the new era of precision oncology.

Abbreviations

ΔΨm

Mitochondrial membrane potential

Akt

Protein kinase B

AMPK

AMP-activated protein kinase

Atg8

Autophagy-related gene 8

ARG1

Arginase 1

ATP

Adenosine triphosphate

Bax

Bcl-2-associated X protein

Bak

Bcl-2 antagonist/killer 1

Bcl-2L13

BCL2-like protein 13

BLCA

Bladder cancer

BRCA

Breast cancer

CAF

Cancer-associated fibroblast

CAMK1α

Calcium/calmodulin-dependent protein kinase 1α

CAMKII

Calcium/calmodulin-dependent protein kinase II

Caspase-3/9

Cysteine-aspartic acid protease-3/9

CDK1

Cyclin-dependent kinase 1

CDK5

Cyclin-dependent kinase 5

cGAS-STING

Cyclic GMP-AMP synthase-Stimulator of interferon genes

CMT2A

Charcot-Marie-Tooth disease type 2A

COA1

Cytochrome c oxidase assembly factor 1

COAD

Colon adenocarcinoma

COX

Cytochrome c oxidase

COX18

COX assembly protein 18

DCs

Dendritic cells

DDP

Cisplatin

Drp1/DNM1L

Dynamin-related protein 1

ECM

Extracellular matrix

EMT

Epithelial-mesenchymal transition

ER

Endoplasmic reticulum

ERK1/2

Extracellular regulated kinase 1/2

EVs

Extracellular vesicles

F-actin

Filamentous actin

FAK

Focal adhesion kinase

FAO

Fatty acid oxidation

Fis1

Fission protein 1

FUNDC1

FUN14 domain containing 1

GLUT1

Glucose transporter 1

GTP

Guanosine triphosphate

GTPase

Guanosine triphosphatase

HCC

Hepatocellular carcinoma

HDAC6

Histone deacetylase 6

HIF1α

Hypoxia-inducible factor 1α

IMM

Inner mitochondrial membrane

IMS

Intermembrane space

IL-10/IL-12

Interleukin-10/Interleukin-12

INF2

Inverted formin 2

KIF5

Kinesin family member 5

LC3

Microtubule-associated protein 1 light chain 3

LIR

LC3-interacting regions

L-OPA1

Long isoform optic atrophy 1

LUAD

Lung adenocarcinoma

MAPK

Mitogen-activated protein kinase

MARCH5

Membrane-associated ring-CH-type finger 5

MHC-I

Major histocompatibility complex class I

Mdivi-1

Mitochondrial division inhibitor-1

MEFs

Mouse embryonic fibroblasts

MEK

Mitogen-activated protein kinase kinase

Mff

Mitochondrial fission factor

MFN

Mitofusin

MIRO

Mitochondrial Rho GTPase

MiD49/51

Mitochondrial dynamics proteins 49/51

MOMP

Mitochondrial outer membrane permeabilization

mTOR

Mammalian target of rapamycin

mTORC1

Mammalian target of rapamycin complex 1

mtDNA

Mitochondrial DNA

NDP52

Nuclear dot protein 52 kDa

NIX/BNIP3

BCL2/adenovirus E1B 19kDa-interacting protein 3-like

NK cells

Natural killer cells

Noxa

Phorbol-12-myristate-13-acetate-induced protein 1

Nrf2

Nuclear factor erythroid 2-related factor 2

OMM

Outer mitochondrial membrane

OMA1

OMA1 zinc metallopeptidase

OPA1

Optic atrophy 1

OXPHOS

Oxidative phosphorylation

Puma

p53 upregulated modulator of apoptosis

p62/SQSTM1

Sequestosome 1

PD-1

Programmed death 1

PGAM5

Phosphoglycerate mutase family member 5

PINK1

PTEN-induced kinase 1

PKA

Protein kinase A

PKCδ

Protein kinase Cδ

Rho

Ras homolog

ROCK1

Rho-associated coiled-coil containing protein kinase 1

ROS

Reactive oxygen species

S3

15-oxospiramilactone

S3

15-oxospiramilactone

SENP3

Sentrin/SUMO-specific protease 3

S-OPA1

Short isoform optic atrophy 1

SKOV3

Human ovarian adenocarcinoma cell line 3

STAD

Stomach adenocarcinoma

SUMO

Small ubiquitin-like modifier

TAMs

Tumor-associated macrophages

TCA

Tricarboxylic acid

TILs

Tumor-infiltrating lymphocytes

TME

Tumor microenvironment

TNTs

Tunneling nanotubes

TOM

The outer membrane translocase complex

TRAK1/2

Trafficking kinesin protein 1/2

Tregs

Regulatory T cells

UBDs

Ubiquitin-binding domains

ULK1

Unc-51-like autophagy activating kinase 1

USP30

Ubiquitin specific peptidase 30

VDAC1

Voltage-dependent anion channel 1

Author contributions

Aixin Wang and Chao Zhang designed the study, and drafted the manuscript. Xinyu Ye and Yumeng Zhao participated in the revision of the manuscript. Chao Zhang reviewed the manuscript.

Funding information

This work was supported by Beijing Natural Science Foundation (No. 7222157) and the National Natural Science Foundation of China (No. 82003809).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethical approval

Not applicable.

Conflicts of interest

The authors declare no competing interests.

Clinical trial number

not applicable.