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21 September 2025

Mitochondrial DNA Dysfunction in Cardiovascular Diseases: A Novel Therapeutic Target

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1
Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
2
Russian-Chinese Education and Research Center of System Pathology, South Ural State University, 454080 Chelyabinsk, Russia
3
Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Science, 620049 Ekaterinburg, Russia
4
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Antioxidants2025, 14(9), 1138;https://doi.org/10.3390/antiox14091138
This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress
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Abstract

Cardiovascular diseases hinge on a vicious, self-amplifying cycle in which mitochondrial deoxyribonucleic acid (mtDNA) dysfunction undermines cardiac bioenergetics and unleashes sterile inflammation. The heart’s reliance on oxidative phosphorylation (OXPHOS) makes it exquisitely sensitive to mtDNA insults—mutations, oxidative lesions, copy-number shifts, or aberrant methylation—that impair ATP production, elevate reactive oxygen species (ROS), and further damage the mitochondrial genome. Damaged mtDNA fragments then escape into the cytosol, where they aberrantly engage cGAS–STING, TLR9, and NLRP3 pathways, driving cytokine storms, pyroptosis, and tissue injury. We propose that this cycle represents an almost unifying pathogenic mechanism in a spectrum of mtDNA-driven cardiovascular disorders. In this review, we aim to synthesize the pathophysiological roles of mtDNA in this cycle and its implications for cardiovascular diseases. Furthermore, we seek to evaluate preclinical and clinical strategies aimed at interrupting this cycle—bolstering mtDNA repair and copy-number maintenance, reversing pathogenic methylation, and blocking mtDNA-triggered innate immune activation—and discuss critical gaps that must be bridged to translate these approaches into precision mitochondrial genome medicine for cardiovascular disease.

1. Introduction

Mitochondria are highly specialized, double-membrane organelles with cell- and tissue-specific morphology, dynamics, and functions. They play a central role in metabolism and signaling pathways, including energy generation, calcium homeostasis, ROS production, heme synthesis, steroidogenesis, programmed cell death, and metabolite catalysis [1,2,3]. Each mitochondrion contains multiple copies of circular mitochondrial DNA (mtDNA), organized within nucleoids in the inner mitochondrial matrix, and characterized by its own transcriptional machinery [2,4,5]. Animal tissue cells contain thousands of mtDNA copies spread out over hundreds of mitochondria, encoding 13 polypeptides for the respiratory chain complexes, 22 transfer ribonucleic acids (tRNAs), and 2 ribosomal RNAs (rRNAs), as well as enzymes needed for their transcription and translation [2,3,5,6,7]. Notably, mtDNA copies often exceed what is strictly necessary for oxidative phosphorylation, suggesting additional roles in mitochondrial signaling or immune regulation [2]. Like nuclear DNA (nDNA), mtDNA is vulnerable to mutations and exogenous or endogenous damage, which can drive mitochondrial dysfunction and human pathologies [4,8,9,10,11].
Given the heart’s absolute dependence on OXPHOS, mtDNA damage naturally manifests in cardiac syndromes—either as primary mitochondrial disease or as part of multisystem disorders. Clinically, the vicious cycle of bioenergetic failure and sterile inflammation manifests across cardiovascular diseases. In hypertension [12,13,14,15] and atherosclerosis [16,17], mtDNA mutations have been widely reported, and oxidized mtDNA accelerates vascular senescence and exacerbates plaque inflammation. In myocardial ischemia, damaged mtDNA is released and triggers severe inflammatory responses, exacerbating tissue damage [18,19,20,21,22,23,24,25,26]. In heart failure, mtDNA lesions and depletion are involved in critical ATP deficits and worsen contractile dysfunction [27,28]. In diabetic cardiomyopathy, fatty acid-driven mtDNA release provokes cardiomyocyte pyroptosis via the cGAS–STING pathway [29,30]. Arrhythmias, too, are associated with oxidative lesions and mutations in mtDNA [31,32]. Thus, mtDNA has emerged as a critical target for mechanistic understanding and therapeutic innovation in cardiovascular medicine. Elucidating the molecular pathways linking mtDNA integrity to disease progression may open new avenues for biomarker development and precise interventions.
In this review, we synthesize the physiological and pathological features of mtDNA, propose a unified “vicious cycle” theory linking mtDNA dysfunction to cardiac bioenergetic collapse and sterile inflammation, and highlight emerging therapeutic strategies and remaining challenges. Our goal is to inform the development of systematic, mtDNA-targeted interventions that mitigate myocardial injury, prevent heart failure, and reduce mortality.

2. Overview of mtDNA

The origin of mitochondria as an ancient archaeal endosymbiont endows the organelle with its own double-stranded, circular genome [33]. This autonomous genome retains the machinery needed to replicate, transcribe, and translate its genes, thereby allowing mitochondria to self-regulate critical functions such as energy production, signaling, and apoptosis (Figure 1).
Figure 1. Physiological properties of mitochondrial DNA (mtDNA). (A) Gene distribution in mtDNA, with 28 genes on the heavy (H) strand and 9 on the light (L) strand. (B) MtDNA replication occurs in the ‘replisome’ comprising DNA polymerase γ, mitochondrial single-stranded DNA binding protein, Twinkle helicase, topoisomerases, and TFAM. (C) Transcription of mtDNA initiated at the D-loop region is regulated by POLRMT, TFAM, and TFB2M, producing 13 mRNAs, 22 tRNAs, and 2 rRNAs. (D) MtDNA-directed translation involves initiation complex assembly, mRNA binding to the ribosomal subunit, tRNA-mediated peptide elongation, translation termination, and ribosome recycling. (E) MtDNA-encoded polypeptides contribute to the function of ETC, specifically within complexes I, III, IV, and V.

2.1. Structure of mtDNA

MtDNA exists as a closed, circular duplex with a purine-rich heavy (H) strand and a pyrimidine-rich light (L) strand [3,4]. It contains 37 genes-28 on the H-strand and 9 on the L-strand-that are directly or indirectly involved in ATP synthesis via oxidative phosphorylation [3,5,34]. Unlike the nDNA counterpart, mtDNA is extraordinarily gene-dense (~93% coding), with overlapping reading frames and only one major non-coding region, the displacement loop (D-loop), which harbors the origin of replication and promoters for transcription [3].
Rather than being wrapped around histones, mtDNA is packaged into 100-nm nucleoids through binding to the nuclear-encoded mitochondrial transcription factor A (TFAM) [4,35]. TFAM is imported into mitochondria via an N-terminal mitochondrial targeting peptide that is cleaved upon entry to form mature TFAM. In the mitochondrial matrix, TFAM coats mtDNA to stabilize its structure and binds the D-loop to coordinate the bidirectional transcription from the light-strand promoter (LSP) and two heavy-strand promoters (HSP1, HSP2) [4,36,37].

2.2. MtDNA Replication, Transcription, and Translation

MtDNA replication occurs continuously, independent of the cell-division cycle, and is entirely governed by nuclear-encoded factors [3]. In eukaryotes, mtDNA replication takes place within a “replisome” complex whose catalytic core is DNA polymerase γ (POLγ), accompanied by two accessory subunits [3,5]. This machinery also includes the mitochondrial single-stranded DNA-binding protein (mtSSB), which stabilizes unwound DNA and enhances POLγ activity; the Twinkle helicase/primase; various topoisomerases; and TFAM, which may protect mtDNA from oxidative damage [3]. Mammalian mtDNA replicates mainly by a strand-displacement mechanism: synthesis of the heavy (H) strand initiates at the D-loop origin and proceeds unidirectionally until exposing the light (L)-strand origin, at which point L-strand synthesis begins in the opposite direction. Both strands elongate asynchronously until two daughter molecules are complete [38,39].
Transcription of mtDNA is driven by three promoters: the light-strand promoter (LSP) and two heavy-strand promoters (HSP1, HSP2) [37]. Nuclear-encoded mitochondrial RNA polymerase (POLRMT) forms a pre-initiation complex with TFAM and TFB2M at the D-loop, melting DNA to expose each promoter [40,41]. From HSP2 and LSP, genome-length polycistronic transcripts are produced; the H-strand is additionally transcribed from promoter HSP1 to generate a shorter transcript consisting of two rRNAs and two tRNAs [42]. Transcript elongation is carried out by POLRMT, with assistance from the mitochondrial transcription elongation factor, while termination is regulated by mitochondrial transcription termination factor 1 (MTERF1) [3].
The mitochondrial ribosomes utilize a unique set of translation initiation, elongation, and termination factors, culminating in a translation cycle completely different from the bacterial and cytosolic ones [43,44]. Initiation factor mtIF-3 dissociates ribosomal subunits to allow assembly of the initiation complex, aligning the start codon of mRNA on the small subunit’s P-site [3,45]. Peptide elongation is mediated by nuclear-encoded mitochondrial elongation factor Tu (tRNA delivery) and mitochondrial elongation factor G (mRNA–tRNA translocation and ribosome recycling) [3,46,47,48,49,50]. Termination relies on mitochondrial release factor 1 (mtRF1), which recognizes stop codons and catalyzes peptide release [3,45].

2.3. MtDNA in OXPHOS System

The mitochondrial OXPHOS system serves the fundamental purpose of ATP transduction by oxidizing fuel molecules via the respiratory electron transport chain (ETC) [7]. The mammalian ETC comprises five multimeric complexes (Complexes I–V) embedded in the inner mitochondrial membrane [51]. These complexes harness energy released from electron transfer from NADH or FADH2, largely generated by the tricarboxylic acid cycle-to pump protons across the inner mitochondrial membrane, creating a proton-motive force that Complex V uses to synthesize ATP [51,52,53].
Although the majority of OXPHOS subunits are encoded in the nucleus, translated in the cytosol, and imported into mitochondria [7,37,51], mtDNA encodes 13 indispensable polypeptides that belong to four of the five complexes (I, III, IV, and V) [3,7,37,54]. In total, 92 structural OXPHOS subunits-13 mtDNA-encoded and 79 nDNA-encoded-assemble into a highly coordinated machinery [3,34].
Complex I contains 44 subunits (7 mtDNA-encoded ND1-ND6, ND4L, and 37 nDNA-encoded), Complex II is entirely nDNA-encoded (4 subunits), Complex III includes one mtDNA-encoded cytochrome b plus 10 nDNA-encoded subunits, Complex IV comprises three mtDNA-encoded (COI–COIII) and 11 nDNA-encoded proteins, and Complex V (ATP synthase) contains two mtDNA-encoded (ATPase6, ATPase8) and 17 nDNA-encoded subunits [3,34,55,56]. Together, nDNA- and mtDNA-encoded components orchestrate efficient electron flow and prevent accumulation of harmful assembly intermediates [51].

3. MtDNA Dysfunction in Cardiovascular Diseases

In the heart, mitochondrial oxidative metabolism supplies approximately 90% of cellular ATP, underlining its centrality to cardiovascular function [57]. Cardiac mtDNA governs both the mitochondrial lifecycle and the integrity of the oxidative phosphorylation system [58]. Excess ROS in cardiomyocytes and endothelial cells inflicts irreversible mtDNA damage, leading to mutations that further impair OXPHOS and disrupt mitophagy. Such dysfunction precipitates the escape of mtDNA and mitochondrial proteins into the cytosol, activating innate immune pathways and driving tissue injury [57,58]. These intra- and extra-mitochondrial mtDNA–mediated processes (Figure 2 and Figure 3) highlight mtDNA as a compelling therapeutic target. Table 1 provides representative examples of distinct cardiovascular pathologies driven by mtDNA abnormalities, summarizing their underlying mechanisms and the supporting evidence.
Figure 2. MtDNA-related pathological processes within mitochondria. (A) Forms of mtDNA mutations, include base-pair substitutions, rearrangements, duplications, deletions, and insertions. (B) Methylation of mtDNA in the D-loop region, involves methyl group addition and leads to transcriptional repression. (C) Representative oxidative modifications of mtDNA affect both the sugar-phosphate backbone and the four nucleotide bases.
Figure 3. MtDNA release from mitochondria and its physiological and pathological effects outside the organelle. (A) Mechanisms of mtDNA release. MtDNA release occurs via multiple pathways: inner mitochondrial membrane herniation into the cytoplasm; oligomerization of VDACs forming outer membrane pores; leakage through the MPTP; mitochondria-derived vesicles; and excessive mitochondrial fission or rupture. (B) Autophagic Clearance of mtDNA. Autophagy begins with phagophore formation and expansion mediated by PINK1, Parkin, adaptor, and lipidated LC3B-II. The resulting autophagosomes subsequently fuse with lysosomes for mtDNA degradation. (C) mtDNA-Induced Inflammation. Cytosolic mtDNA activates innate immunity via TLR9–NFκB–NLRP3 signaling, leading to elevated inflammatory cytokines, and through the cGAS–cGAMP–STING axis, leading to TBK1/IKK-mediated IRF3 and NFκB activation. This promotes type I interferon and proinflammatory cytokine production (D) Pyroptosis pathway. NLRP3 inflammasome activation cleaves pro-caspase-1 into caspase-1, which processes pro-IL-1β and pro-IL-18 into active forms. Caspase-1 also cleaves GSDMD, generating the N-terminal fragment (GSDMD-N) that forms membrane pores, facilitating the secretion of IL-1β and IL-18 and leading to pyroptotic cell death.

3.1. MtDNA Oxidative Damage

Any damage, especially oxidative damage to mtDNA can alter mitochondrial transcripts and impair oxidative phosphorylation [59]. Mitochondria are significant sources of ROS in cells [60,61] and mtDNA is a major target for ROS-mediated damage due to its proximity to the principal ROS source, the inner mitochondrial membrane [9,62]. Other factors contributing to mtDNA’s susceptibility include the absence of protective histone proteins, limited mtDNA repair activity, retention of superoxide anions within mitochondria, and the negatively charged environment of the mitochondrial matrix [9,59,63,64]. ROS can oxidize bases and the sugar-phosphate backbone of mtDNA or incorporate oxidized bases during DNA polymerization [26,65]. If incompletely repaired, DNA nicks and abasic sites accumulate, blocking mtDNA transcription and replication [26].
Susceptibility to oxidative damage follows the base reactivity order G > C > T >> A, with guanine being the most prone to oxidation, leading to 8-oxo-guanine formation and subsequent G-A mismatches [66,67]. Oxidative-generated DNA modifications have been systematically reviewed elsewhere [64,68]. Hydroxyl radicals readily attack the 2′-deoxyribose, creating carbon-centered sugar radicals that lead to strand incision and unique products (base propenal, 3′-phosphoglycolate, 5′-aldehyde) [64]. Although purine 8,5′-cyclo-2′-deoxyribonucleosides can form via sugar-base radical addition, they have not yet been detected in mtDNA [64]. On pyrimidines, hydroxyl radicals add at C5 or C6 to yield C5–OH–C6 or C6–OH–C5 pyrimidine radicals and downstream redox products [64,68]. The principal purine modification is C8 addition, producing 2,6-diamino-4-hydroxy-5-formamidopyrimidine/4,6-diamino-5-formamidopyrimidine or 8-hydroxy-guanine/8-oxo-7,8-dihydroguanine/8-oxo-7,8-dihydroadenine through different redox pathways [64,69]. Moreover, oxidative stress compromises mitochondrial integrity, promoting the release of modified mtDNA into the cytosol [67].
In most cardiovascular diseases, elevated ROS levels increase mtDNA damage and reduce oxidative phosphorylation [21,31,70,71]. Both clinical and animal studies demonstrate a tight link between mtDNA lesions and mitochondrial dysfunction in myocardial remodeling and heart failure [8,9,63]. Reports indicate oxidative mtDNA damage rises by over 50% in failing hearts [10]. The common mtDNA4977 deletion, a hallmark oxidative lesion, accumulates with age in human hearts and during vascular aging and atherosclerosis [72,73]. In atherosclerosis, conditions such as hyperglycaemia and smoking may further promote mtDNA damage via ROS [74,75], and such damage compromises metabolism, fostering endothelial dysfunction and pro-atherogenic phenotypic changes in vascular smooth muscle cells (VSMC) [11]. Notably, leukocyte levels of 8-hydroxy-2′-deoxyguanosine, an oxidative purine product, predict coronary artery disease risk in type 2 diabetes [69]. As the most common macrovascular complication of diabetes, atherosclerosis also involves ROS-mediated DNA strand breaks [76], with damage accumulating from early lesions and escalating with disease progression [77].
Beyond oxidative insults, non-oxidative mtDNA damage also contributes to cardiovascular diseases: heart failure arises from heart-specific mutant uracil-DNA glycosylase 1 expression [78], and atherosclerosis can result from ROS-independent mtDNA damage in smooth muscle cells and monocytes [75]. Additionally, cardiac hypertrophy, fibrosis, and failure occur following primary mtDNA damage induced by homozygous POLG mutations or prolonged zidovudine treatment [79,80].

3.2. MtDNA Mutations

Mutations in the mitochondrial genome give rise to a wide spectrum of diseases, the majority of which are maternally inherited and involve defects in oxidative energy metabolism [81,82]. MtDNA mutation rate significantly exceeds that of nDNA owing to increased oxidative damage, frequent replication errors, inefficient repair mechanisms, and absence of histone protection [83,84]. In adults, mtDNA mutations account for approximately 70% of mitochondrial diseases [85]. Depending on their location, these mutations may impair specific respiratory-chain proteins or disrupt overall mitochondrial protein synthesis if affecting tRNA or rRNA genes [86].
MtDNA mutations are broadly classified as point mutations or large-scale rearrangements [86]. Most point mutations occur in tRNA genes, with tRNALeuUUR and tRNAIle representing “hotspots” for cardiomyopathy-associated mtDNA variants [7]. Rearrangements are typically heteroplasmic, coexisting with varying proportions of wild-type genomes [7]. Under normal conditions, pathogenic mtDNA variants constitute less than 1% of the total mtDNA pool, rendering tissues effectively homoplasmic for the wild-type sequence [85,86]. MtDNA mutation only manifests clinically once its heteroplasmic load exceeds a tissue-specific threshold-often above 60%—which varies according to the reliance of each tissue on oxidative metabolism [7,85,87]. Consequently, the severity of cellular or tissue dysfunction and the overall phenotypic expression of mtDNA disease are largely determined by the mutant-to-wild-type genome ratio [7,85,88].
MtDNA mutations are strongly associated with cardiovascular disease [7], with specific examples including mtDNA abnormalities in dilated cardiomyopathy [89], increased mtDNA deletions in atrial fibrillation [31], the MTTL1 m.3243A>G mutation and sudden cardiac death [90], and small deletions or heteroplasmic length variants in chronic atrial fibrillation [32]. Notably, approximately 20% of known pathogenic mtDNA point mutations are linked to cardiomyopathy, with tRNA mutations, particularly in tRNALeuUUR and tRNAIle-constituting recognized hotspots [7]. Pathogenic variants in tRNAIle (m.4277T>C, m.4295A>G, m.4300A>G, m.4320C>T) are associated with mitochondrial hypertrophic cardiomyopathy, while m.4269A>G causes encephalocardiomyopathy and m.4317A>G leads to fatal infantile cardiomyopathy [91]. The m.3243A>G mutation in tRNALeuUUR commonly induces MELAS syndrome, frequently involving cardiac manifestations such as hypertrophic cardiomyopathy or Wolff-Parkinson-White syndrome [7,92]. Additionally, transgenic models support a causal role: accelerated accumulation of mtDNA mutations in mice recapitulates human disease phenotypes, including premature aging, dilated cardiac hypertrophy, and fatal congestive heart failure [93]. Kearns–Sayre syndrome—caused by mtDNA rearrangements—demonstrates how impaired energy supply disrupts high-demand tissues [7,94].
Together, these findings highlight the central role of mtDNA mutations-especially those affecting tRNA genes-in the pathogenesis of mitochondrial cardiomyopathies.

3.3. MtDNA Copy-Number Variations

MtDNA copy-number varies among individuals and even among different tissues within the same individual [95], serving as a candidate biomarker of mitochondrial function that reflects both mitochondrial abundance per cell and genome copies per mitochondrion [63,96]. MtDNA depletion, defined as a reduction to less than 30% of normal levels [91], arises from impaired biogenesis or excessive loss due to enzyme deficiencies [97], defective nucleotide metabolism [98], loss of mitochondrial fusion [99], drug toxicity [100,101,102], and other causes. Depletion disrupts the mitochondrial network, reduces cristae membrane content, and leads to a circular morphology of the remaining cristae [103].
Conversely, in response to mitochondrial dysfunction, nuclear-encoded factors may drive disproportionate mitochondrial biogenesis, leading to over-replication of the mtDNA and mitochondrial proliferation [95]. Accordingly, increased mtDNA copy-number in mitochondrial diseases may represent a compensatory mechanism to alleviate bioenergetic deficits, delay disease onset, and modulate phenotypic severity [95,104]. This compensatory increase helps explain why patients harboring high loads of deletion mutants sometimes present with only mild mitochondrial myopathy [95].
In humans, mtDNA content correlates positively with mitochondrial gene transcription and serves as an indicator of mitochondrial dysfunction [80]. Reduced mtDNA copy-number underlies severe cardiac disorders such as cardiomyopathy [91], pathological cardiac remodeling [105,106], atrial fibrillation [107], and heart failure [10,108]. Certain chemotherapeutic agents-including doxorubicin [100,101,102] and nucleoside reverse transcriptase inhibitors [109,110]—exert cardiotoxicity by inhibiting DNA replication and depleting mtDNA. In Chagasic cardiomyopathy, poly (ADP-ribose) polymerase 1 translocates to mitochondria and binds mitochondrial POLγ, impairing mtDNA maintenance and exacerbating mitochondrial dysfunction, oxidative stress, and cardiac remodeling [105]. A case of severe dilated mitochondrial cardiomyopathy was linked to a novel homoplasmic tRNAIle mutation accompanied by profound mtDNA depletion [91]. Additionally, patients with heart failure of diverse etiologies exhibit reduced mtDNA content alongside decreased levels of mtDNA-encoded proteins [111].

3.4. MtDNA Methylation

Epigenetic mechanisms produce heritable phenotypic changes via chromosome modifications rather than alterations in DNA sequence, enabling adaptive responses to environmental stimuli [40,112]. Among these, DNA methylation is the most extensively studied modification and plays a pivotal role in establishing cellular identity. Dysregulated mtDNA methylation has been implicated in aging and various diseases [41,113,114]. MtDNA methylation involves transfer of a methyl group from S-adenosyl methionine to DNA bases, with primarily adenine in the D-loop of the light (L) strand [4,114,115]. Increased methylation in this region generally suppresses transcription [4], thereby affecting mitochondrial quality control and often triggering the integrated stress response [116]. DNA methyltransferases (DNMTs) mediate mtDNA methylation, with DNMT1 being the most abundant and active form throughout adulthood [116]. DNMT1 harbors a mitochondrial targeting sequence, which directs its import into mitochondria, where it binds mtDNA and catalyzes D-loop methylation [117,118]. Upregulation of mitochondrial DNMT1 exerts gene-specific effects: it represses ND6 (the sole protein-coding gene on the L strand) while enhancing ND1 expression on the H strand [41]. Both ND1 and ND6 encode subunits of complex I critical for cardiac contractility [119]. Recent advances in detection methods have identified N6-methyldeoxyadenine (6mA)—a methylation mark once thought restricted to bacteria—in eukaryotes [120]. Its regulatory role in mitochondrial stress has been reported [120,121]. Methyltransferase-like protein 4 (METTL4), a putative mammalian methyltransferase, catalyzes mtDNA 6mA methylation, leading to repression of transcription and reduction in mtDNA copy-number [121].
Although the prevalence and functional significance of mtDNA methylation remain debated, numerous studies have documented correlations between mtDNA methylation (and hydroxymethylation) patterns and cell type, differentiation state, age, and disease status [4,41]. In metabolically active organs such as the heart, altered mtDNA methylation impacts bioenergetics and can promote systemic inflammation, vascular endothelial dysfunction, and myocardial injury [116]. The methylation and downregulation of mitochondrial gene COX2, which encodes COII, are biomarkers of aging in heart mesenchymal stem cells [122]. Moreover, in platelets from patients with cardiovascular disease, increased methylation of mtDNA encoding cytochrome c oxidase and tRNA leucine 1 has been reported [123]. Mitochondrial-targeted overexpression of DNMT1 also impairs mitochondrial gene expression, compromises mitochondrial function, and reduces VSMC contractility [118]. Finally, mtDNA methylation appears to influence clinical presentation in coronary artery disease: patients with acute coronary syndrome exhibit higher mtDNA methylation and lower mtDNA copy-number compared to those with stable coronary artery disease [124].

3.5. MtDNA Release

Under stress, mitochondria can release mtDNA into the cytosol, where it acts as a damage-associated molecular pattern (DAMP) and triggers inflammation [52,125]. During apoptosis, pro-apoptotic proteins BAX and BAK promote mitochondrial outer membrane permeabilization (MOMP), allowing release of intermembrane-space proteins—such as cytochrome c—and subsequent activation of caspases, culminating in cell death [126,127]. However, cell death can also proceed via caspase-independent pathways, which are accompanied by mtDNA leakage [126]. When caspases are inhibited, BAX/BAK-mediated MOMP drives herniation of the inner mitochondrial membrane into the cytosol, carrying matrix components, including mtDNA [126,128,129]. Rather than preventing herniation, apoptotic caspases function to clear dying cells and suppress mtDNA-induced innate immune signaling via the cGAS–STING pathway, thereby maintaining immunological silence during apoptosis [129].
Large mitochondrial membrane pores can also form independently of BAX/BAK. Under oxidative stress, voltage-dependent anion channel 1 (VDAC1)—the most abundant outer-membrane protein, which regulates Ca2+ influx, metabolism, inflammasome activation, and cell death—oligomerizes to create large pores that facilitate mtDNA release [130]. It has been proposed that VDAC1 oligomers mediate mtDNA efflux under moderate stress, whereas BAX/BAK macropores predominate during severe stress or apoptosis [130]. Another debated mechanism involves the mitochondrial permeability transition pore (MPTP), a nonspecific 2–3 nm inner-membrane channel formed in response to Ca2+ overload and other stimuli [66,131]. The MPTP permits passage of molecules smaller than ~1500 Da and may allow egress of mtDNA fragments [66], although its precise role remains controversial and is sometimes conflated with VDAC1 function [131,132].
Mitochondria-derived vesicles have also been suggested as carriers of mtDNA; these small vesicles bud from mitochondria carrying proteins and lipids while preserving membrane integrity [131,133]. However, evidence for mtDNA incorporation into mitochondria-derived vesicles and its subsequent release into the cytosol to activate cGAS remains limited [131]. Finally, excessive mitochondrial fission can disrupt membrane integrity, causing rupture and release of mtDNA into the cytosol [18].
Myocardial mitochondrial dysfunction and consequent mtDNA release are crucial pathophysiological hallmarks or mediating factors for the pathogenesis of myocarditis [134], post-MI cardiac dysfunction [18], myocardial ischemia/reperfusion injury (MI/RI) [23], and thrombosis [135]. Perfusion of the coronary circulation with mtDNA fragments during heart ischemia increases infarct size, underscoring mtDNA’s cardiotoxic potential [26]. In an atherosclerosis mouse model, oxidized mtDNA is released via VDAC1-dependent MPTP opening and activates the STING–PERK pathway [132]. Similar interactions between released mtDNA and inflammation have been observed in animal models of hypertension [15] and doxorubicin-induced cardiotoxicity [136]. Circulating mtDNA has also been proposed as a blood-based biomarker for atrial fibrillation [137].
The lipotoxicity-mediated mtDNA release has also been reported. Upon cellular entry, fatty acids may be esterified into triglycerides for storage in lipid droplets [138,139]. Upon demand, stored triacylglycerols are released and hydrolyzed into fatty acids, which are subsequently converted to fatty acyl-CoA [139]. While fatty acyl-CoA normally undergoes β-oxidation in mitochondria to support energy production, cardiac cells may also divert it toward the synthesis of harmful lipids such as ceramides, diacylglycerols, and triglycerides [140]. The resulting lipid accumulation causes lipotoxicity, promoting endoplasmic reticulum stress, apoptosis, and inflammation [138]. Importantly, lipotoxicity can trigger mtDNA release, activating cGAS–STING signaling and inflammatory pathways, ultimately leading to cardiac cell death and fibrosis [29,30].

3.6. Autophagy

Autophagy serves as another line of defense when insults overwhelm the protective antioxidant, repair pathways, and inhibition of mtDNA release. This homeostatic mechanism sequesters harmful cytosolic components within double-membrane autophagosomes, which subsequently fuse with lysosomes to degrade their contents [125,141]. Under low-energy conditions, AMP-activated protein kinase (AMPK) is activated and phosphorylates ULK1 (unc-51–like kinase 1), initiating phagophore formation. This curved double membrane structure expands via autophagy-related (ATG) proteins into a mature autophagosome [127]. Microtubule-associated protein 1 light chain 3 beta (LC3B), a member of the ATG8 family, integrates into the growing phagophore and drives membrane elongation, of which LC3B-I turns into lipidated form termed LC3B-II that binds to the phagophore [127].
Mitophagy, the selective removal of damaged mitochondria, begins when PTEN-induced kinase 1 (PINK1) accumulates on the outer mitochondrial membrane and recruits Parkin. Parkin ubiquitinates mitochondrial surface proteins, facilitating recruitment of LC3-binding adaptors and targeting mitochondria for autophagic degradation [142]. Upon mitochondrial stress, PINK1 directly phosphorylates and activates Parkin on Ser65 in its ubiquitin-like domain, which leads to ubiquitination of substrates on damaged mitochondria that function as autophagy-mediated degradation signals [143]. Mitophagy mediated by this signaling pathway attenuates pathological cardiac alternation via inhibiting the mtDNA release [144,145]. On the other hand, although PINK1 and Parkin are not encoded by mitochondrial genes, the 3733G>C mutation in mtDNA downregulated PINK1/Parkin-mediated mitophagy pathway [146]. In selective autophagy, autophagy adaptors act as selective takers, which contain both a ubiquitin-binding domain for recognizing ubiquitin chains and an LC3-interacting region for recruiting phagophore membranes [143]. During mitophagy, all known autophagy adaptors are recruited to damaged mitochondria in a PINK1/Parkin-dependent manner [147].
In addition to mitochondrial proteins functioning as substrates of PINK1/Parkin-mediated ubiquitination, mitophagy also relies on various mitochondrial cargo receptors, including BCL2-interacting protein 3 (BNIP3), BNIP3-like protein (BNIP3L, known as NIX), FUN14 domain containing 1(FUNDC1), and others [148,149]. BNIP3 and NIX function primarily under stress, which integrate into the outer mitochondrial membrane via their carboxy terminal transmembrane domains, with the remaining bulk of both proteins facing into the cytosol, where a conserved LC3 interaction region near the amino-terminal end interacts with processed LC3/GABARAP [148]. NIX undergoes ubiquitylation by Parkin to facilitate recruitment of the autophagy adaptor NBR1, which promotes formation of autophagosomes surrounding mitochondria by simultaneously binding to ubiquitin and LC3/GABARAP, while BNIP3 interacts with and stabilizes PINK1 on the outer mitochondrial membrane, leading to Parkin translocation to mitochondria [143]. Cardiac progenitor cells harboring mtDNA mutations fail to efficiently activate the mitophagy in response to differentiation, while this adverse situation is fortunately improved by NIX-and FUNDC1-mediated mitophagy [149].
Autophagosomes carrying impaired mitochondria fuse with the lysosomes and deoxyribonuclease (DNase) degrades mtDNA in the autophagy system to eliminate damaged mtDNA [141,150,151]. However, mtDNA that escapes autophagic clearance elicits inflammatory responses mediated by toll-like receptor (TLR) 9, the NLRP3 inflammasome, or the cGAS-STING pathway [16,125,141,152]. TLR9 recognizes unmethylated CpG motifs in mtDNA delivered to lysosomes by autophagosomes [153,154]; intriguingly, TLR9 activation via this route also contributes to mitochondrial biogenesis, suggesting context-dependent roles based on the source of the TLR9 ligand and how or where the receptor/ligand interaction takes place [154]. Meanwhile, autophagy proteins regulate innate immune responses by limiting NLRP3 inflammasome-mediated mtDNA release [125].
Apoptosis-induced autophagy can occur independently of caspase activation: BAX/BAK-mediated mitochondrial permeabilization rapidly activates AMPK and ULK1, driving autophagic flux that degrades mitochondria and reduces mtDNA release and downstream innate immune signaling [127]. However, it is suspected that cGAS/STING activation occurs too quickly for autophagic clearance to inhibit this early step effectively. For this question, the authors speculated that BAX/BAK-stimulated autophagy causes the cytokine to be sequestered rather than released, but it remains to be determined [127]. Moreover, STING itself can induce autophagy from the ER-Golgi intermediate compartment, as evidenced by LC3 lipidation and autophagosome formation, although the precise mechanism remains unclear [128]. We hypothesize that STING activation at the ER-Golgi intermediate compartment stimulates the local production of autophagy-specific phosphoinositides or facilitates the transfer of lipids to create a lipid microenvironment conducive to the elongation and curvature of phagophores. Because phosphatidylinositol 4-phosphate, the most abundant cellular phosphoinositide with the highest abundance at the trans-Golgi network, is an energy source for lipid-transfer [155]. Lipid transfer plays a critical role in membrane remodeling and is directly implicated in autophagy [156].
Physiologically, mitophagy maintains mitochondrial quality by removing damaged organelles. In some metabolic disorders and cardiovascular diseases, mitophagy is often impaired, leading to the accumulation of dysfunctional mitochondria, elevated mtDNA fragments, and chronic inflammation [157]. For instance, mtDNA, if escaping from autophagy, can provoke inflammation in cardiomyocytes, even myocarditis, and dilated cardiomyopathy [141]. In atherosclerotic plaques, endogenous mtDNA complexed with LL-37 evades DNase II and autophagic degradation, persistently activating TLR9 and driving chemokine and cytokine production that exacerbates lesion development [16]. Similarly, impaired mitophagy facilitates NLRP3 inflammasome activation in atherosclerosis [158], and in silica nanoparticle exposure-induced cardiac adverse events, defective autophagic flux permits cytosolic mtDNA accumulation and cGAS-STING-mediated pyroptosis [152]. During myocardial ischemia/reperfusion or hypoxia/reoxygenation, autophagy deficiency promotes mitochondrial fission, mtDNA release, and sterile inflammation, i.e., the activation of the STING/IRF3 axis [24].

3.7. Inflammation

Because mtDNA contains unmethylated CpG motifs similar to bacterial DNA, it elicits stronger inflammatory responses than nDNA [16]. When mtDNA enters the cytosol, extracellular space, or circulation, it activates multiple pattern-recognition receptors, triggering pro-inflammatory and type I interferon responses [2]. Different mtDNA topology affects different inflammatory responses of cardiomyocytes [159]. As a prototypical DAMP, mtDNA–driven sterile inflammation plays a central role in the pathogenesis of diverse cardiovascular diseases [160,161].
Endolysosomal TLR9 recognizes unmethylated CpG motifs in mtDNA released from injured cells. Upon binding mtDNA, TLR9 initiates a signaling cascade that activates nuclear factor-κB (NFκB) and induces expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, as well as assembly of the NLRP3 inflammasome [125,141,160,162,163,164,165]. In the injured heart, these cytokines elevate intracellular ROS, which further compromise mitochondrial membrane integrity and exacerbate cell death [134]. NLRP3 activation itself appears to depend on hexokinase dissociation from mitochondria, thereby promoting the oligomerization of voltage-dependent anion channel (VDAC) on the outer membrane; together with cytosolic mtDNA fragments, oligomerized VDAC recruits NLRP3 to the mitochondrial surface for inflammasome assembly [166]. Oxidized mtDNA released during apoptosis can also directly bind and activate NLRP3 in primed macrophages, driving IL-1β secretion [167].
The cGAS-STING signaling pathway senses pathogenic DNA and initiates a tightly regulated signaling cascade to trigger various inflammatory effectors [30,168]. Cytosolic mtDNA is sensed by cGAS, which catalyzes synthesis of 2′,3′-cyclic GMP-AMP (2′,3′-cGAMP) from ATP and GTP upon DNA binding [128,169]. cGAMP then functions as a secondary messenger activating STING, leading to phosphorylation of interferon regulatory factor 3 (IRF3) and NFκB via the TANK-binding kinase 1 (TBK1) and I-kappa-B kinase (IKK), respectively [30,128,168]. Phosphorylated IRF3 dimerizes and translocates to the nucleus to drive type I interferon transcription [33], while NFκB initiates the transcription of pro-inflammatory cytokines implicated in atherosclerosis, pulmonary arterial hypertension, and myocarditis [132,134,170]. In addition, it may also be involved in metabolic regulation by rewiring the metabolic circuitry, such as ornithine decarboxylase-putrescine metabolic flux [171]. Beyond these canonical pathways, STING can also activate PERK in endothelial cells [132], engage MAPKs, stimulate NLRP3, trigger autophagy, and even induce lytic cell death, underscoring its multifunctional role in inflammation and cell fate [128,157,168].
Clinically, robust myocardial infarction (MI)-mediated inflammation contributes to adverse remodeling and dysfunction across cardiovascular contexts. In this process, cGAS-STING-driven macrophage polarization toward an M1 phenotype exacerbates tissue damage and remodeling; conversely, inhibiting this axis enhances wound healing, neovascularization, and survival post-MI [19,20]. Additionally, NFκB activated by the STING, transactivates ornithine decarboxylase-putrescine metabolic flux to prompt the pathogenesis of cardiac hypertrophy [171]. In hypertension, elevated circulating mtDNA coupled with impaired DNase activity activates TLR9, raising arterial pressure and promoting vascular dysfunction [172]. In atherogenesis, ROS-induced mtDNA damage and release fuel vascular inflammation and VSMC phenotypic switching [17,77], while VCAM1-mediated aberrant mtDNA synthesis in macrophages triggers STING-dependent inflammation and lesion progression [173]. Similarly, STING signaling drives VSMC senescence and fibrous-cap thinning in chronic-kidney-disease-associated atherosclerosis [174]. Finally, activated NLRP3 in cardiomyocytes promotes collagen deposition, left ventricular hypertrophy, fibrosis, and diastolic dysfunction [30].

3.8. Pyroptosis

Pyroptosis is an inflammatory form of programmed cell death characterized by caspase-1-dependent formation of membrane pores, resulting in the release of pro-inflammatory cytokines IL-1β and IL-18 [21]. This process is closely linked to activation of the NLRP3 inflammasome, a multimeric complex composed of NLRP3, the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), and caspase-1 [21]. Upon assembly, the inflammasome cleaves pro–caspase-1 into active caspase-1, which in turn processes pro-IL-1β and pro–IL-18 into their mature forms and simultaneously cleaves gasdermin D (GSDMD) to generate the pore-forming N-terminal fragment (GSDMD-N). GSDMD-N mediates secretion of IL-1β and IL-18 and disrupts plasma membrane integrity, culminating in pyroptotic cell death [30,175].
In cardiovascular pathology, NLRP3 inflammasome activation and elevated IL-1β/IL-18 levels drive recruitment of macrophages to aortic lesions, promoting foam-cell formation and plaque progression [176]. Within the myocardium, NLRP3 inflammasome activation in cardiac fibroblasts stimulates IL-1β release and cardiomyocyte pyroptosis, exacerbating cardiac inflammation and adverse remodeling [158]. Additionally, this inflammatory cascade and pyroptosis have been observed in myocardial ischemia [21].
Metabolic stress further accentuates pyroptosis in the heart. In diabetic cardiomyopathy, free fatty acid–induced mtDNA release into the cytosol activates cGAS–STING, triggering pyroptosis and inflammatory responses that drive cardiac hypertrophy [30]. Similarly, exposure to silica nanoparticles disrupts autophagy, leading to cytosolic mtDNA accumulation and cGAS–STING–dependent pyroptosis, as described above [152]. Intriguingly, recent data suggest that cGAS–STING–NLRP3–mediated pyroptosis may enhance the efficacy of radiotherapy in hypertrophic cardiomyopathy, highlighting context-dependent roles for this pathway [177].
Table 1. Representative examples of cardiovascular pathologies driven by mtDNA abnormalities.
Table 1. Representative examples of cardiovascular pathologies driven by mtDNA abnormalities.
Clinical ConditionMechanismEvidence/ExampleReference(s)
HypertensionMtDNA mutations; released mtDNA activates innate immune responses, contributing to vascular dysfunctionm.A14696G and m.A14693G mutations lead to failure in tRNAGlu metabolism[12]
m.15992A>G and m.15077G>A mutations may disturb mitochondrial function[13]
m.T10410C and m.T10454C mutations affect the structure and function of tRNAArg[14]
Released mtDNA mediates inflammation[15]
Elevated circulating mtDNA and impaired DNase activity activate TLR9[172]
AtherosclerosisDamaged mtDNA escapes autophagy and promotes vascular inflammation and VSMC senescenceMtDNA promotes atherosclerosis through mitochondrial dysfunction[71]
MtDNA4977 deletion is a hallmark oxidative lesion, accumulating in vascular aging and atherosclerosis[72,73]
Atherosclerosis can result from ROS-independent mtDNA damage in smooth muscle cells and monocytes[75]
Oxidized mtDNA is released and activates the STING–PERK pathway[132]
MtDNA complexed with LL-37 evades autophagic degradation[16]
Impaired mitophagy facilitates NLRP3 inflammasome activation[158]
ROS-induced mtDNA damage and release promote vascular inflammation and VSMC phenotypic switching[11,17,77]
Aberrant mtDNA synthesis in macrophages exacerbates STING-dependent inflammation and atherosclerosis[173]
STING signaling drives VSMC senescence and fibrous-cap thinning[174]
NLRP3 inflammasome activation and elevated IL-1β/IL-18 levels drive recruitment of macrophages to aortic lesions, promoting foam-cell formation and plaque progression[176]
MtDNA repair can regulate NLRP3 inflammasome and prevent atherosclerosis[178]
Myocardial infarctionDamaged mtDNA is released and triggers severe inflammatory responses, exacerbating tissue damageMyocardial mitochondrial impairment, mtDNA release, and subsequently STING/p65 activation mediate post-MI cardiac dysfunction[18]
cGAS functions as a cytosolic DNA receptor, promoting macrophage polarization and governing myocardial ischemic injury[19,20]
PCSK9 initiates mtDNA damage, and induces pyroptosis[21]
Protection of mitochondria and mtDNA can ameliorate isoproterenol-induced MI[22]
Myocardial ischemia/reperfusion injuryDNA methylation, mtDNA damage, and release amplify sterile inflammationAge-associated DNA methylation augments cardiac sensitivity towards MI/RI[119]
Increased mtDNA release enhances pro-inflammatory cytokines[23]
Autophagy deficiency promotes mitochondrial fission, mtDNA release, and sterile inflammation[24]
ROS can initiate DNA single-strand breakage and severe lesions subsequently[25]
Perfusion of coronary circulation with free mtDNA fragments aggravates infarct[26]
Heart FailureMtDNA lesions, mutations, and depletion impairing OXPHOS and ATP productionOxidative mtDNA damage mediates cardiac dysfunction[9]
ROS increase can lead to a catastrophic cycle of mtDNA damage and cellular injury in heart failure[63]
MtDNA toxicity can impair dynamics and function of mitochondria, leading to heart failure[78]
Angiotensin II-mediated mtDNA oxidative damage, homozygous POLG mutations, or prolonged zidovudine treatment contribute to cardiac hypertrophy, fibrosis, and failure[79]
Accumulation of mtDNA mutations induces premature aging, dilated cardiac hypertrophy, and fatal congestive heart failure[93]
MtDNA copy number depletion is an independent risk factor for heart failure[108]
Reduced mtDNA replication and depletion of mtDNA impair mitochondrial biogenesis[10]
Patients with heart failure exhibit reduced mtDNA content and mtDNA-encoded proteins[111]
TFAM overexpression ameliorates mitochondrial deficiencies, increases mtDNA copy-number, and improves cardiac failure[27,28,179]
Diabetic CardiomyopathyHyperglycemia induces mtDNA oxidative damage and release, activating cGAS-STING-mediated pyroptosisLeukocyte levels of 8-hydroxy-2′-deoxyguanosine predict coronary artery disease risk in type 2 diabetes[69]
Oxidized mtDNA release and triggering cGAS-STING-mediated pyroptosis[30]
Diabetic cardiomyopathy reduces mtDNA replication and transcription, together with impairing mitochondrial ultrastructure[180]
Greater mtDNA damage is found in patients with diabetes mellitus and clinical atherosclerosis[76]
Cardiac HypertrophyMtDNA mutations, mtDNA damage and chronic inflammation promote fibrosis and hypertrophyMutations in tRNAIle including m.4277T>C, m.4295A>G, m.4300A>G, m.4320C>T[91]
Oxidative stress-derived mtDNA damage and deletion are partly linked to cardiac hypertrophy[72]
MtDNA lesions cause a vicious cycle with decreased cardiac bioenergetics and ROS accumulation[80]
NFκB activated by the STING, prompts cardiac hypertrophy[171]
Dilated cardiomyopathyMtDNA mutations and impaired autophagic fluxPathological mtDNA mutations leading to abnormal mitochondria[89]
A homoplasmic tRNAIle mutation accompanied by profound mtDNA depletion[91]
MtDNA that escapes from autophagy provokes myocarditis and dilated cardiomyopathy[141]
ArrhythmiaMtDNA oxidative lesions, mutations, and copy-number variationsOxidative lesions and mtDNA deletions in cardiomyocytes are increased in atrial fibrillation[31]
Kearns–Sayre syndrome, caused by large-scale mtDNA rearrangements, leads to progressive conduction system degeneration.[7,94]
MtDNA mutations are detected in patients with chronic atrial fibrillation[32]
MtDNA copy-number is a risk factor for atrial fibrillation[107]
OthersMtDNA mutationsm.3243A>G mutation of MTTL1 in sudden cardiac death[90]
m.4269A>G mutation causes encephalocardiomyopathy and m.4317A>G leads to fatal infantile cardiomyopathy[91]
m.3243A>G mutation in tRNALeuUUR commonly produces MELAS syndrome[7,92]
MtDNA copy-number variationsIn Chagasic cardiomyopathy, poly (ADP-ribose) polymerase 1 impairs mtDNA maintenance[105]
MtDNA methylation abnormalityThe methylation and downregulation of COX2 are biomarkers of aging in heart mesenchymal stem cells[122]
Altered mtDNA methylation can promote systemic inflammation, vascular endothelial dysfunction, and myocardial injury[116]
Overexpression of DNMT1 impairs mitochondrial gene expression, compromises mitochondrial function, and reduces VSMC contractility[118]
MtDNA releaseImpaired mitochondria and released mtDNA mediate myocarditis[134]
Released mtDNA induces platelet activation, leading to thrombosis[135]
Impaired autophagy, mtDNA release, and pyroptosisIn cardiomyocytes exposed to silica nanoparticles, defective autophagic flux permits cytosolic mtDNA accumulation and cGAS-STING-mediated pyroptosis[152]
PyroptosisNLRP3 activation in cardiac fibroblasts stimulates cardiomyocyte pyroptosis, exacerbating cardiac inflammation and adverse remodeling[158]

5. Conclusions and Perspectives

In conclusion, mtDNA dysfunction constitutes a self-perpetuating vicious cycle at cardiovascular pathogenesis, mechanistically linking bioenergetic collapse to sterile inflammation. This cycle acts both as an instigator in susceptible individuals and an amplifier of injury in established disease. Disrupting this deleterious cycle requires a two-pronged therapeutic approach: alleviating mtDNA pathological characteristics and suppressing innate immune activation.
Despite these promising strategies, key questions remain unresolved. In some settings, mtDNA defects may be downstream consequences rather than primary causes. The heteroplasmy thresholds at which mutant mtDNA becomes pathogenic are poorly defined and most proposed therapies have not advanced beyond preclinical models. Rigorous mechanistic investigations and well-designed clinical trials will be essential to establish causality, identify at-risk patient populations, and translate this unified pathogenic framework into effective treatments.
Ultimately, future work must integrate mtDNA-focused diagnostics with targeted therapies to break this pathogenic cycle and improve cardiovascular outcomes.

Author Contributions

M.X. and M.Y.: Data curation, Writing-original draft, Investigation, Conceptualization. X.O., A.S. and S.L.: Methodology, Writing-review & editing, Conceptualization, Validation. L.Z. and D.H.: Writing-review & editing, Validation, Supervision, Resources, Project administration, Funding acquisition, Conceptualization. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundations of China (Nos. 82474287, 82274317, 82070136).

Conflicts of Interest

The authors confirmed that there is no conflict of interest.

Abbreviations

ROS, reactive oxygen species; mtDNA, mitochondrial deoxyribonucleic acid; tRNA, transfer ribonucleic acid; rRNA, ribosomal ribonucleic acid; H-strand, heavy strand; L-strand, light strand; ATP, adenosine triphosphate; nDNA, nuclear DNA; D-loop, displacement loop; TFAM, mitochondrial transcription factor A; TFB2M, mitochondrial transcription factor B2; POLRMT, mitochondrial RNA polymerase; POLγ, polymerase γ; LSP, light strand promoter; HSP, heavy strand promoter; OXPHOS, oxidative phosphorylation; ETC, electron transport chain; DNMT1, DNA methyltransferase 1; VSMC, vascular smooth muscle cell; cGAS, cyclic GMP-AMP synthase; STING, stimulator of interferon genes; GTP, guanosine triphosphate; cGAMP, cyclic GMP-AMP; MPTP, mitochondrial permeability transition pore; MI, myocardial infarction; MI/RI, myocardial ischemia/reperfusion injury; AMPK, AMP-activated protein kinase; LC3, microtubule-associated protein 1 light chain 3; DNase, deoxyribonuclease; TLR, toll-like receptor; NLRP3, nucleotide-binding domain and leucine-rich-repeat family pyrin domain containing 3; DAMP, damage-associated molecular pattern; IRF3, interferon regulatory factor 3; NFκB, nuclear factor kappa B; TBK1, TANK-binding kinase 1; IKK, I-kappa-B kinase; ASC, apoptosis-associated speck-like protein containing a CARD; GSDMD, gasdermin D; BER, base-excision repair; OGG1, 8-oxoguanine glycosylase; SIRT, sirtuin; Endo III, endonuclease III; NADH, nicotinamide adenine dinucleotide; FADH2, flavin adenine dinucleotide; PPAR, peroxisome proliferator activated receptor; COX, cytochrome c oxidase; LC3B, microtubule-associated protein 1 light chain 3 beta. PINK1, PTEN-induced kinase 1; BNIP3, BCL2 interacting protein 3; BNIP3L, BNIP3-like protein/Nip3-like protein X (NIX); FUNDC1, FUN14 domain containing 1.

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