Mitochondrial Dysfunction in Myeloid Cells: A Central Deficit in Autoimmune Diseases

Abstract

Autoimmune diseases arise from genetic and environmental factors that disrupt immune tolerance. Recent studies highlight the role of myeloid cell immunometabolism, particularly mitochondrial dysfunction, in driving autoimmunity. Mitochondria regulate energy homeostasis and cell fate; their impairment leads to defective immune cell differentiation, abnormal effector activity, and chronic inflammation. We propose that chronic metabolic stress reprograms myeloid cells, fueling a vicious cycle of cell death and immune activation. Over time, this may induce several states of maladaptation in myeloid cells. Viewing autoimmune disease through a metabolic lens offers new insight into disease mechanisms and highlights potential therapeutic opportunities targeting mitochondrial function to restore immune balance.

Mitochondrial Control of Myeloid Cell Fate in Autoimmunity

Autoimmune diseases constitute over one hundred known heterogenous disorders characterized by aberrant immune responses against autoantigens, leading to organ and tissue damage [1]. Representing a significant public health burden, there is an increasing need for targeted therapeutics [2,3]. While substantial advances in the development of disease-modifying antirheumatic drugs (DMARDs) and biologics have been made, the fundamental pathophysiological mechanisms leading to the loss of self-tolerance remain incompletely understood. The prevailing dogma is that the pleiotropic contributions of genetic predisposition, epigenetic modifications, and environmental triggers promote successive failures in the regulation of innate and adaptive effector immune responses [4].

Over the past decade, there has been mounting evidence implicating dysregulation of myeloid cells (predominantly dendritic cells (DCs), macrophages, and neutrophils), as critical to the initiation and perpetuation of autoimmunity [5] (Table 1). In this opinion article, we propose that mitochondrial dysfunction is a central defect in myeloid cells that contributes to the initiation and progression of autoimmune diseases and its associated organ damage. As frontline responders of the innate immune system, myeloid cell populations are uniquely positioned to initiate the early stage of autoimmune disease pathogenesis, modulated by genetic and environmental factors. Emerging evidence suggests that these cells undergo metabolic reprogramming to sustain chronic inflammation. Given their critical role as hubs of cellular bioenergetics, mitochondria orchestrate a tightly regulated network that integrates metabolic and immune signaling. Disruption of this network can lead to overactivation of myeloid cells, fueling persistent inflammatory responses. Moreover, the resulting cycle of cellular stress and death releases immunogenic material, further exacerbating immune dysregulation. We argue that this persistent dysfunction ultimately drives myeloid cells into multiple maladaptive states. We focus specifically on mitochondrial dysfunction, rather than general metabolic stress, as a mechanistic driver of chronic myeloid cell activation and maladaptation in autoimmunity. Although systemic lupus erythematosus (SLE) remains the prototypical systemic autoimmune disease, this review also includes some examples of organ-specific autoimmune diseases in which dysfunctional myeloid metabolism has been implicated.

Table 1:

Dysregulated Myeloid Cell Populations Implicated in Autoimmune Diseases and Evidence of Mitochondrial Involvement (Where Available).

Disease	Species & model studied	Myeloid cell population(s)	Key features of dysfunction	Reference
Systemic lupus erythematosus (SLE)	Murine (IMQ driven model)	CD138+ CD317+ pDCs CD11b+ Ly6G+ neutrophils CD11b+ CD11c+ inflammatory monocytes	Increased NET deposition Increased oxidized circulating DNA STING activation & type I IFN	[42]
	Human (active SLE) Murine (IMQ driven model)	CD177hi neutrophils CD177hi LDGs	Enhanced ROS (cytosolic & mitochondrial) production Enhanced NET production	[80]
	Human (cutaneous lupus) Nonhuman primate	HLA-DR+ CD123+ BDCA-2+ pDCs	Enhanced type I IFN activity in local tissue	[81]
	Murine (IMQ driven model)	pDCs with NCF1 missense variant	Enhanced capability to produce type I IFNs, TNFα, IL-6, MHC II upon TLR stimulation	[82]
	Human (active SLE) Murine (MRL/MpJ-Faslpr/J model)	Proinflammatory LDGs	NETosis driven by ROS (mitochondrial) Release of interferogenic mtDNA	[41]
	Human (mix of active/inactive SLE)	CD15+ PD-L1+ neutrophils	Frequency of PD-L1+ neutrophils correlated with disease activity and severity	[52]
Psoriatic arthritis (PsA)	Human	‘Exhausted’ CD62Llo neutrophils	Increased neutrophil-related effector molecules (MMP-9, TNF, IL-23, IL-17) Increased citrullinated histone H3 CD66b and CD11b upregulation upon TNF stimulation	[50]
Rheumatoid arthritis (RA)	Human (high severity RA)	Synovial fluid neutrophils	Increased chemokine and ROS (cytosolic) Enhanced survival Increased NET production	[83]
	Human		Increased oxidative stress and mtDNA release Increased RANKL expression	[84]
	Human	CD14+ monocytes	Enhanced mitochondrial respiration Altered mitochondrial morphology Increased glycolytic enzymes	[85]
Psoriasis	Human	CD14lo CD15hi CD10hi LDGs	Induced endothelial damage Correlates with noncalcified coronary plaque burden	[86]
Sarcoidosis	Human	TREM2+ macrophages	Hypermetabolic Increased PPP enzymatic activity	[26]

IMQ, imiquimod; pDC, plasmacytoid dendritic cell; NET, neutrophil extracellular trap; IFN, interferon; LDG, low density granulocyte; TNF, tumor necrosis factor; IL, interleukin; mtDNA, mitochondrial DNA; STING, stimulator of interferon genes; MMP-9, matrix metalloproteinase-9; MHC II, major histocompatibility complex class II; RANKL, receptor activator of nuclear factor kappa B ligand; PD-L1, programmed death-ligand 1; NCF1 neutrophil cytosolic factor 1; TLR, toll-like receptor; TREM2, triggering receptor expressed on myeloid cells 2; PPP, pentose phosphate pathway; ROS, reactive oxygen species – includes mitochondrial or cytosolic origin as specified.

Mitochondria are the Central Hubs of Myeloid Cell Bioenergetics

Immunometabolism, the metabolic framework that modulates immune cell behavior, is fundamental to the regulation of cell states, cell fate decisions, and effector function [6]. Immunometabolic responses must be highly adaptable due to rapid changes in microenvironment, developmental state, and other cues faced by immune cells. Central to this metabolic network is the mitochondrion (Figure 1), long recognized for its role in the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS). However, mitochondrial function extends well beyond energy production; it integrates diverse metabolic pathways and regulates key processes such as reactive oxygen species (ROS; see Glossary) synthesis, redox homeostasis, and cell death [7].

Figure 1: Immunometabolism in Myeloid Cells Converges on Mitochondrial Function.

Myeloid cells rely on tightly regulated immunometabolic pathways to maintain homeostasis and support key effector functions during activation. Mitochondria serve as central hubs in this network, integrating multiple energy-generating processes including glycolysis, the tricarboxylic acid (TCA) cycle, and the electron transport chain (ETC), ultimately driving cellular respiration and ATP production. TCA cycle intermediates feed into ETC complex I and II, with ROS generated downstream during electron transfer. ROS is produced by both NADPH oxidase and mitochondria. In parallel, glucose-6-phosphate can be diverted into the pentose phosphate pathway (PPP), generating NADPH required for ROS detoxification and nucleotide biosynthesis. Amino acids are imported through specific transporters and converge on the mammalian target of rapamycin complex (mTORC), which regulates fatty acid oxidation and feeds into the TCA cycle. mTORC activity, modulated by AMP-activated protein kinase (AMPK), also governs cytokine and chemokine production, cytoskeletal remodeling, and cell survival. These metabolic programs engage in dynamic crosstalk with nuclear transcriptional regulators that shape cell differentiation, maturation, and immune effector functions. Mitochondrial mass and function are both regulated by, and contribute to, these transcriptional networks. Finally, immunometabolic responses are further influenced by genetic polymorphisms, environmental exposures, and sex hormones. Created in https://BioRender.com

Disruption of physiological mitochondrial function in immune cells, termed mitochondrial dysfunction, signifies a breakdown in these tightly regulated bioenergetic and signaling systems [8]. In autoimmunity, a growing body of evidence implicates mitochondrial dysfunction in both the onset, and persistence of diseases including SLE, rheumatoid arthritis (RA), Kawasaki disease, progressive systemic sclerosis, and Sjogren syndrome [9–12]. The mechanisms underlying this dysfunction are diverse and multifactorial, ranging from genetic susceptibilities, environmental insults, impaired OXPHOS, oxidative stress, mitochondrial component leakage, impaired mitophagy, and pro-inflammatory cell death. While these pathways are incompletely elucidated, they offer critical insight into the metabolic underpinnings of chronic autoimmune inflammation, and highlight mitochondria as central players in pathogenesis [13].

Genetic and Environmental Contributors of Myeloid Mitochondrial Dysfunction

The genetic underpinnings of mitochondrial dysfunction are important factors to consider in the context of directing myeloid effector function. In some cases, mitochondrial disorders may clinically mimic autoimmune diseases, underscoring the importance of differential diagnosis [14]. Beyond this phenotypic overlap, mitochondrial respiration plays a direct role in antigen processing [15], and genetic risk alleles may influence both antigen presentation and the metabolic programming of myeloid cells. Such alleles can impair mitochondrial function, disrupting key immunometabolic pathways. Importantly, somatic mutations in mitochondrial peptides have also been proposed as triggers of early loss of self-tolerance in SLE [16]. These mitochondrial perturbations could represent initiating or amplifying events in autoimmunity.

Environmental factors further shape myeloid cell development through mitochondrial modulation. The marked female predominance observed in many autoimmune diseases implicates the influence of X-linked genes and sex hormones [17]. It is well established that estrogen promotes myeloid differentiation by enhancing granulocyte-macrophage colony-stimulating factor (GM-CSF) production, thereby driving the maturation of myeloid progenitors into macrophages, DCs, and neutrophils [18,19]. In contrast, androgens are immunosuppressive [20], associated with delayed neutrophil maturation. Male neutrophils exhibit a more immature phenotype, with increased mitochondrial DNA (mt-DNA) content, mitochondrial mass, and OXPHOS activity compared to females, highlighting sex-specific differences in immunometabolism [21]. During pregnancy, a state of hormonal fluctuation, neutrophils display immature characteristics and altered mitochondrial profiles [22]. These findings suggest that sex hormone signaling directly modulates myeloid cell maturation and mitochondrial dynamics, potentially contributing to increased autoimmune susceptibility in females. Taken together, these studies demonstrate that both genetic and environmental factors can modulate mitochondrial function, thereby shaping myeloid cell development and function in ways that may promote autoimmunity.

Mitochondrial Stress and DAMPs as Triggers of Myeloid Cell Activation

The importance of mitochondrial integrity in maintaining physiological myeloid cell function cannot be understated. Indeed, mitochondrial ROS production is vital for macrophage and neutrophil antimicrobial functions. Although cytosolic ROS production via NADPH oxidase is distinct from mitochondrial ROS, both can contribute to oxidative stress and downstream immune activation [23]. Mitochondria regulate redox homeostasis through multiple pathways, including antioxidant systems and control of ROS, while cytosolic NADPH production via the pentose phosphate pathway (PPP) also plays a central role in maintaining cellular redox balance. NADPH supports the activity of thioredoxin and glutathione reductases, enabling efficient hydrogen peroxide detoxification [24,25]. The PPP is especially active in monocytes and macrophages, where it promotes proinflammatory M1 polarization and is implicated in granuloma formation in diseases such as sarcoidosis [26,27]. In glomerulonephritis, PPP activation correlates with macrophage gene expression profiles [28]. Conversely, PPP inhibition can enhance macrophage-mediated lymphoma clearance through the UDP-glucose–Stat1–Irg1–itaconate axis [29]. These diverse roles underscore the central importance of PPP-mediated redox balance in regulating myeloid cell function.

Myeloid cells experience heightened oxidative stress during autoimmunity (Figure 2). In SLE, mitochondrial stress induces the cytoplasmic release of mtDNA through voltage-dependent anion channel (VDAC) oligomerization. This activates the cyclic GMP-AMP synthase - stimulator of interferon genes (cGAS-STING) pathway promoting proinflammatory responses. Inhibition of VDAC oligomerization reduces hallmark lupus features and ameliorates mitochondrial ROS in monocytes and NETosis in low-density granulocytes (LDGs, a subtype of neutrophils implicated in the pathogenesis of SLE and other systemic rheumatic diseases) [30]. Mitochondrial stress also contributes to oxidative damage and endothelial injury in SLE, effects that can be exacerbated by tissue hypoxia [31,32]. Under these conditions, mitochondrial ROS stabilize hypoxia-inducible factor 1-alpha (HIF-1α), a key transcription factor that promotes glycolysis and influences myeloid cell survival [33]. Indeed, HIF-1α has been implicated in diverse, context-dependent effects on myeloid cell function and survival [34].

Figure 2: Mitochondrial Dysfunction Results in Widespread Myeloid Cell Dysregulation.

Representative figure of mechanisms implicated in dysfunction of multiple myeloid cell populations (neutrophils, dendritic cells, macrophages/monocytes). Disruption of mitochondrial homeostasis leads to the release of highly immunostimulatory danger-associated molecular patterns (DAMPs), including succinate from the tricarboxylic acid (TCA) cycle, cardiolipin, and mitochondrial DNA (mtDNA). These molecules escape into the cytosol through oligomerization of voltage-dependent anion channel 1 (VDAC1), triggering innate immune pathways. Notably, mtDNA activates the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) axis, mimicking the response to viral nucleic acids via mitochondrial antiviral-signaling protein (MAVS). This activation drives transcription of type I interferon (IFN) genes through downstream effectors such as Interferon Regulatory Factor 3 (IRF3) and Nuclear Factor kappa B (NF-κB), leading to a pronounced IFN signature, a metabolic shift from oxidative phosphorylation (OXPHOS) to sustained glycolysis, and dysregulated immune effector responses. cGAS-STING signaling also activates the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, promoting pyroptotic cell death via gasdermin D (GSDMD). In parallel, excessive production of reactive oxygen species (ROS)—driven in part by NADPH oxidase—exceeds the buffering capacity of mitochondria, further amplifying oxidative stress. Mitochondrial dysfunction also stabilizes hypoxia-inducible factor 1-alpha (HIF-1α), supporting cellular survival under stress but enhancing proinflammatory potential. In autoimmune diseases such as lupus, cell-free mtDNA and nuclear DNA released during aberrant NETosis can serve as autoantigens, promoting autoantibody production. Compounding this, impaired mitophagy and defective clearance of dying cells (efferocytosis) result in the persistence of these DAMPs, perpetuating a self-sustaining cycle of immune activation and tissue damage. Created in https://BioRender.com

Moreover, mitophagy, the process by which dysfunctional mitochondria are cleared, is impaired in various cells in individuals with SLE and may contribute to chronic inflammation. In murine models of SLE, compounds that promote mitophagy have shown beneficial effects in inducing mitophagy in myeloid cells, restoring mitochondrial function, and reducing disease severity. This study also demonstrated that inducing mitophagy improved myeloid cell function and reduced inflammatory burden [35]. The accumulation of damaged mitochondrial components due to defective mitophagy alters the local tissue microenvironment and influences both the metabolism and function of myeloid cells.

As innate immune first responders, myeloid cells detect pathogens and cellular damage via pattern recognition receptors (PRRs), which recognize both pathogen-associated and damage-associated molecular patterns (PAMPs and DAMPs). Under mitochondrial stress, mitochondrial DAMPs (such as cardiolipin, mtDNA, and succinate) are released and act as potent immune activators [36–38]. Recent studies underscore a bidirectional relationship between mitochondrial integrity and myeloid cell activation in autoimmune diseases [39–44]. NETs, a major source of DAMPs, are key drivers of sterile inflammation in SLE, RA and other autoimmune diseases [39]. NETs contain proinflammatory components, including oxidized mtDNA, which can trigger type I interferon (IFN) responses via the cGAS-STING pathway [41]. Importantly, STING deficiency in lupus-prone mice reduces myeloid cell expansion and confers vascular protection [42]. Beyond innate sensing, type I IFN signaling has been shown to remodel macrophage metabolism by inhibiting isocitrate dehydrogenase, thereby altering the TCA cycle following lipopolysaccharide (LPS) stimulation [44]. Moreover, in plasmacytoid dendritic cells (pDCs) derived from FLT3 ligand-stimulated bone marrow cultures, type I IFNs promote increased OXPHOS and fatty acid oxidation, linking IFN signaling to metabolic reprogramming in key immune subsets [45].

A central feature in the development of autoimmunity is the dysregulation of various forms of cell death, along with impaired clearance of dying cells (Figure 3). This results in the release and prolonged half-life of modified autoantigens, as well as repeated exposure to mitochondrial DAMPs, which together amplify immune activation. Mitochondria play a well-established role in apoptosis, regulated by caspases and BCL-2 family proteins. Notably, defects in the PPP can impair efferocytosis, the clearance of apoptotic cells, thereby increasing the exposure to DAMPs and perpetuating inflammation [46,47]. Beyond apoptosis, mitochondria also facilitate proinflammatory forms of cell death, including necroptosis and pyroptosis, and mitochondrial dysregulation is associated with enhanced proinflammatory NET formation in the context of autoimmune diseases [38]. Numerous studies demonstrate how dysregulated cell death promotes excessive ROS formation and conversely, how mitochondrial dysfunction induces proinflammatory cell death accompanied by the modification and externalization of autoantigens [48,49]. These findings reveal a direct link between mitochondrial dysfunction and inflammatory cell death in myeloid cells within autoimmune settings.

Figure 3: Mitochondrial Dysfunction Drives Distinct Maladaptive States in Myeloid Cells.

During chronic autoimmunity mitochondrial dysfunction serves as a central pathogenic node that contributes to maladaptive myeloid cell responses in chronic autoimmune disease. This schematic illustrates how mitochondrial dysfunction, proinflammatory cell death, and persistent immune cell activation can drive the emergence of three potential functional states: A) Exhaustion, characterized by reduced phagocytic capacity and cytokine responsiveness; B) Senescence, marked by cell-cycle arrest and acquisition of a senescence-associated secretory phenotype (SASP); and C) Trained immunity, in which metabolic and epigenetic reprogramming of the myeloid cell lineage leads to exaggerated inflammatory responses. Each of these states contributes to immune dysregulation, loss of tolerance, and progression toward autoimmune pathology. Arrows denote that mitochondrial dysfunction, proinflammatory cell death, and persistent immune activation are interrelated, and are upstream of these phenotypes; the figure does not imply hierarchical progression among the states. Created in https://BioRender.com

In summary, multiple lines of evidence indicate that, in genetically predisposed individuals, myeloid cells are subject to diverse stressors that collectively impair mitochondrial function and promote the release of proinflammatory mediators.

Myeloid Cell Maladaptation in Chronic Autoimmunity Driven by Mitochondrial Dysfunction

Our current understanding of myeloid hyperactivation and mitochondrial dysfunction has primarily centered on their roles in acute and subacute inflammation. However, the natural history of many autoimmune diseases is marked by years, if not decades, of chronic immune stimulation. We propose that this persistent activation may drive three possible maladaptive responses in myeloid cells, analogous to those observed in adaptive immunity (Figure 3). We further reason that these maladaptive responses are driven by the long-term consequences of sustained mitochondrial dysfunction.

First, we propose that chronic autoimmune activation, exacerbated by mitochondrial dysfunction, may induce a state of functional exhaustion in terminally differentiated myeloid cells and/or their precursors. Although exhaustion is well-defined in lymphocytes, emerging evidence suggests that chronic mitochondrial stress may impair myeloid cell function through sustained ROS exposure and bioenergetic depletion. Indeed, data from models of chronic sterile inflammation suggest that prolonged stimulation can lead to progressive impairment in myeloid cell function [50,51]. In SLE, specific neutrophil subsets exhibit signs of bioenergetic dysfunction and heightened proinflammatory activity, consistent with an exhausted phenotype [50]. Some of these neutrophils also express elevated levels of canonical exhaustion markers, which correlate with disease severity [52]. Similar features of exhaustion have been observed in pDCs in established SLE, including diminished cytokine production and impaired T cell activation [53]. In aged mice, conventional myeloid DCs display mitochondrial abnormalities, such as reduced membrane potential, decreased OXPHOS, increased proton leak, and elevated ROS, alongside impaired phagocytosis and antigen presentation [54]. Macrophages may also enter a hypophagic state, exhibiting reduced antibody-dependent phagocytosis after repeated opsonization [55]. Mechanistic insights from in vitro studies in murine memory monocytes suggest that CD38 upregulation leads to intracellular nicotinamide adenine dinucleotide (NAD⁺) depletion and reduced mitochondrial respiration, providing a potential driver of functional exhaustion [56]. Collectively, these findings support the hypothesis that chronic immune activation may drive myeloid exhaustion across multiple subsets, neutrophils, DCs, and macrophages, ultimately impairing regulatory functions and contributing to autoimmune progression.

Second, we highlight evidence suggesting that cellular senescence, especially in DCs and monocytes, may be induced by mitochondrial dysfunction in chronic autoimmune settings. Senescence is characterized by irreversible cell-cycle arrest and the acquisition of a senescence-associated secretory phenotype (SASP), which can further promote tissue inflammation. There is growing recognition of senescent myeloid populations in autoimmune and inflammatory diseases. For instance, senescent myeloid cells have been identified within the neuronal microenvironment of murine models of multiple sclerosis [57]. In SLE, pDCs with shortened telomeres and transcriptional signatures of senescence and cellular stress are detectable even at preclinical stages [53]. Bioinformatic analyses of lupus nephritis kidney tissue have identified senescence-associated genes such as ALOX5, PTGER2, and PRKCB as potential diagnostic markers [58]. The mechanisms by which mitochondrial dysfunction drives senescence are beginning to emerge. Mitochondrial dysfunction itself is a known inducer of the SASP axis. [59]. Additionally, mitochondrial biogenesis appears to be essential for SASP expression in the aging liver, and reducing mitochondrial content can mitigate this phenotype [60]. Impaired mitophagy is also an early hallmark of stress-induced senescence in mouse models [61]. Beyond this, it is also known that neutrophils contribute to cellular aging and induce senescence in local microenvironments through ROS production [62]. Counter to this, there are also reports of immunosuppressive senescent-like neutrophils being beneficial in settings of bone formation [63] and the tumor microenvironment [64]. These observations suggest that mitochondrial dysfunction may detrimentally promote senescence in a subset of DCs and monocytes, though the significance of senescent-like neutrophils in autoimmunity remains to be further elucidated.

Third, we emphasize the role of trained immunity, a form of innate immune memory, as a potential driver of chronic autoimmunity through mitochondrial metabolic reprogramming. Trained immunity involves long-lasting changes in myeloid responses due to epigenetic and metabolic imprinting, either at the level of bone marrow progenitors (central training) or circulating monocytes/macrophages (peripheral training) [65]. In central training, hematopoietic stem cells in SLE exhibit transcriptional reprogramming and a myeloid-biased differentiation profile, which may prime the immune system toward sustained activation [66]. In murine models of systemic sclerosis, Bacillus Calmette–Guérin (BCG) vaccination has been shown to induce trained immunity that worsens fibrosis and inflammation [67]. Mitochondrial metabolism plays a central role in trained immunity by supporting epigenetic and metabolic reprogramming of myeloid progenitors [68,69]. In peripheral contexts, monocytes exposed to autoantigens and autoantibodies may also acquire a trained phenotype. In RA, synovial autoantibodies can induce trained immunity in infiltrating monocytes in vitro [70]. Similarly, in SLE, exposure of monocytes to NET-derived nuclear antigens and apoptotic microparticles promotes a trained immune response [71]. These monocytes display increased mitochondrial mass, enhanced TCA cycle activity, and a hyperinflammatory cytokine profile [72]. These data suggest that trained immunity, whether initiated centrally or peripherally, can perpetuate immune activation in autoimmunity, with mitochondrial metabolism serving as a central regulatory node.

Taken together, these emerging areas, myeloid exhaustion, senescence, and trained immunity, represent distinct but potentially intersecting outcomes of chronic immune stimulation and mitochondrial dysfunction. Each process contributes to persistent immune dysregulation, and their crosstalk with immunometabolic pathways offers a promising direction for future investigation into both the mechanisms and therapeutic targets of autoimmune disease.

Therapeutic Potential of Targeting Mitochondrial Dysfunction in Myeloid Cells

Directly addressing mitochondrial dysfunction in myeloid cells offers a promising therapeutic strategy for restoring immune tolerance in autoimmune diseases. Growing evidence from both preclinical and clinical studies supports the utility of mitochondria-targeted interventions in modulating myeloid cell behavior and reducing disease activity.

Preclinical evidence:

Several studies have demonstrated that correcting mitochondrial stress can attenuate key pathogenic mechanisms in autoimmunity in lupus-prone mice. For example, the mitochondrial-targeted antioxidant MitoQ reduced neutrophil ROS production and NET formation, decreased type I IFN levels, and led to diminished immune complex deposition in renal tissue [73]. Similarly, idebenone, a synthetic analogue of coenzyme Q10 (CoQ10), reduced mortality and disease activity in murine models through improved mitochondrial function [74]. In a separate study, administration of analogs of itaconate, a TCA cycle–derived metabolite with immunomodulatory properties, also alleviated immune dysregulation and organ damage, highlighting the therapeutic potential of targeting metabolic rewiring in myeloid cells [75].

Clinical translation:

In humans, N-acetylcysteine (NAC), a potent antioxidant with a well-established safety profile, was shown to significantly reduce disease activity and complications in a double-blinded randomized controlled trial (RCT) involving SLE patients [76]. Similarly, in RA, CoQ10 supplementation suppressed serum tumor necrosis factor (TNF) levels and oxidative stress markers in an RCT involving patients with active disease [77]. Nicotinamide riboside (NR, an NAD⁺ precursor) is another promising compound that inhibits type I IFN and autophagy in monocytes from SLE patients in vitro and for healthy controls in vivo [78].

Repurposed agents and novel mechanisms:

Beyond antioxidants, mitochondrial modulation has also emerged in the context of repurposed therapeutics. Notably, metformin, a common hypoglycemic agent, has been shown in healthy volunteers to inhibit complex I of the ETC in monocytes, thereby suppressing the induction of trained immunity [79].

Clinical implications:

Together, these findings underscore the potential of mitochondrial-targeting therapies to modulate innate immune responses, particularly in myeloid cells. Such agents could ultimately serve as adjuncts to conventional DMARDs and biologic therapies, helping to recalibrate immune homeostasis and enhance long-term disease control.

Concluding Remarks

Elucidating the role of mitochondrial dysfunction in myeloid cells signifies a critical frontier in the search for targeted therapies for autoimmune diseases. Myeloid cells, situated at the intersection of innate immunity and tissue homeostasis, are uniquely poised to initiate and perpetuate the breakdown of immune tolerance under chronic genetic and environmental stress. We propose that persistent mitochondrial stress, characterized by the release of immunogenic mitochondrial components and bioenergetic reprogramming, acts as a key amplifier of pathogenic myeloid activation that can then amplify downstream pathogenic adaptive immunity.

In the context of sustained PRR stimulation and proinflammatory cell death, myeloid cells may enter maladaptive states of functional exhaustion or senescence: states that favor survival and chronic activation at the expense of immunoregulatory function. In conjunction with the effects of trained immunity, these may represent critical turning points in the progression from immune dysregulation to overt, tissue-damaging autoimmunity. While the evidence is still emerging, the therapeutic implications are clear. Mitochondrial pathways exemplify a compelling and underexplored target for immunomodulation, one that may finally allow us to disrupt chronic inflammation at its cellular and metabolic roots.

Glossary

Cyclic GMP-AMP synthase - stimulator of interferon genes (cGAS-STING) pathway

A central pathway within the cytoplasm of immune cells that responds to nucleic acids, triggering the production of antiviral responses

Disease-modifying antirheumatic drugs (DMARDs)

A class of medications, distinct from steroids and nonsteroidal anti-inflammatory drugs, used to slow progression in rheumatological diseases

Exhaustion

A state of immune dysfunction characterized by poor effector function in the context of prolonged exposure to immunogenic components

FLT3 ligand-stimulated bone marrow cultures

An in vitro culture system to study the effects of FLT3 ligand, a cytokine required in hematopoiesis

Glomerulonephritis

Inflammation of the kidney glomeruli, particularly observed in the context of systemic lupus erythematosus (lupus nephritis) and other autoimmune diseases

Interferon (IFN)

A group of cytokines identified with antiviral properties and subdivided into type I (α/β), type II (γ), and type III IFNs

Kawasaki disease

A rare pediatric medium-sized vasculitis primarily involving coronary vessels

Low-density granulocyte (LDG)

A subtype of neutrophils with lower density that conventional neutrophils, particularly implicated in autoimmune diseases with enhanced effector functions

Mitophagy

The physiological process of clearing defective mitochondria

Mitochondrial DNA (mtDNA)

Circular genomic material found within the mitochondrial matrix

Mitochondrial biogenesis

The cellular process of increasing mitochondrial mass/copy number

Neutrophil extracellular Traps (NETs), NETosis

An effector function unique to neutrophils by which strands of DNA and chromatin bound to proteins are extruded in a form of cell death termed NETosis

Nicotinamide adenine dinucleotide (NAD⁺)

A critical coenzyme in cellular metabolism involved in energy production, redox reactions and DNA repair

Plasmacytoid dendritic cell (pDC)

A subtype of dendritic cell that specializes in producing high amounts of type I interferons

Progressive systemic sclerosis

Also known as scleroderma, a progressive autoimmune disease characterized by multisystem inflammation and fibrosis

Reactive oxygen species (ROS)

Reactive and damaging oxygen-containing molecules with unpaired electrons

Rheumatoid arthritis (RA)

Chronic, autoimmune, inflammatory arthritis primarily affecting peripheral and axial joints with systemic involvement

Sarcoidosis

A multisystem inflammatory disease of unknown etiology, characterized by the formation of granulomas (collections of macrophages and giant cells), particularly in the lungs

Senescence

A state adopted by immune cells characterized by low metabolic function, cell cycle arrest, and increased cellular stress

Senescence-associated secretory phenotype (SASP)

A phenotype characterized by secretion of proinflammatory cytokines and growth factors

Sjogren syndrome

A chronic multisystemic autoimmune disease primarily affecting exocrine glands

Systemic lupus erythematosus (SLE)

Also known as lupus, a chronic multisystem autoimmune disease that primarily affects women, with variable clinical presentation and potential for multi-organ damage

Trained immunity

A form of immunological memory described in innate cells, often involving metabolic reprogramming of precursor cells to enhance future response to prior stimuli

Voltage-dependent anion channel (VDAC)

An outer mitochondrial membrane channel that oligomerizes and influences cell-fate decisions