Mitophagy in cardiovascular diseases: mechanisms and potential therapies

Mitophagy in cardiovascular diseases: mechanisms and potential therapies | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 20 November 2025 V1 Latest version Share on Mitophagy in cardiovascular diseases: mechanisms and potential therapies Authors : Xin-Yu Hu , Shu-Hong Zhao , Dan Huang , Shi-Ying Wang , Ying Xiong , Pan Wu , Hai-Jie Qi , and Zhen-Guo Ma [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176368158.83446849/v1 394 views 80 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Mitophagy, the selective autophagic degradation of mitochondria, is a critical process for preserving mitochondrial quality and cellular homeostasis in the cardiovascular system. This review systematically outlines the principal molecular mechanisms underlying mitophagy, focusing on the PTEN-induced putative kinase 1 (PINK1)-Parkin pathway and receptor-mediated pathways involving proteins such as BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and FUN14 domain-containing protein 1 (FUNDC1). In various cardiovascular diseases, mitophagy is complex and context dependent. When properly regulated, it exerts a protective role by clearing damaged mitochondria, mitigating oxidative stress, and suppressing inflammatory responses. However, the dysregulation of mitophagy—whether it is insufficient or excessive—can contribute to the exacerbation of disease progression. The therapeutic potential of modulating mitophagy through pharmacological agents, genetic interventions, and lifestyle changes is also examined. However, major challenges remain, including the dualistic nature of mitophagy outcomes, the lack of tissue-specific regulators, and the scarcity of clinically applicable modulators. Advancing our understanding of the multi-level regulatory networks governing mitophagy will be essential for developing targeted therapies to combat cardiovascular diseases (CVDs). Mitophagy in cardiovascular diseases: mechanisms and potential therapies Xin-Yu Hu 1,2 , Shu-Hong Zhao 1,2 , Dan Huang 1,2 , Shi-Ying Wang 1,2 , Ying Xiong 1,2 , Pan Wu 3 , Hai-Jie Qi 4 , Zhen-Guo Ma 2,5 1 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China. 2 Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China. 3 Department of Adult Intensive Care Unit, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, 430070 Wuhan, China. 4 Department of Cardiothoracic Surgery, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science &Technology, 430070 Wuhan, China. 5 Department of General Practice, Renmin Hospital of Wuhan University, 430060, Wuhan, China. Address for Correspondence: Zhen-Guo Ma, MD Department of General Practice, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060 Wuhan, China. E-mail: [email protected] Hai-Jie Qi, MD Department of Cardiothoracic Surgery, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science & Technology, 430070 Wuhan, China E-mail: [email protected] Pan Wu, MD Department of Adult Intensive Care Unit, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, 430070 Wuhan, China E-mail: [email protected] Abstract Mitophagy, the selective autophagic degradation of mitochondria, is a critical process for preserving mitochondrial quality and cellular homeostasis in the cardiovascular system. This review systematically outlines the principal molecular mechanisms underlying mitophagy, focusing on the PTEN-induced putative kinase 1 (PINK1)-Parkin pathway and receptor-mediated pathways involving proteins such as BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and FUN14 domain-containing protein 1 (FUNDC1). In various cardiovascular diseases, mitophagy is complex and context dependent. When properly regulated, it exerts a protective role by clearing damaged mitochondria, mitigating oxidative stress, and suppressing inflammatory responses. However, the dysregulation of mitophagy—whether it is insufficient or excessive—can contribute to the exacerbation of disease progression. The therapeutic potential of modulating mitophagy through pharmacological agents, genetic interventions, and lifestyle changes is also examined. However, major challenges remain, including the dualistic nature of mitophagy outcomes, the lack of tissue-specific regulators, and the scarcity of clinically applicable modulators. Advancing our understanding of the multi-level regulatory networks governing mitophagy will be essential for developing targeted therapies to combat cardiovascular diseases (CVDs). Keywords : mitophagy, cardiovascular diseases, PINK1, BNIP3, therapeutic targeting. Introduction Mitochondrial dysfunction forms the pathogenic foundation of CVDs, the world’s foremost cause of death and illness [1, 2]. Key modifiable risks like hypertension, diabetes, and dyslipidemia exacerbate this process by inducing mitochondrial damage, thereby promoting cellular injury and advancing disease pathology [3]. Within this context, mitophagy acts as an essential quality-control system, safeguarding cellular equilibrium by selectively targeting and disposing of impaired mitochondria [4]. Consequently, the failure of this critical safeguard significantly propels the development of CVDs, including conditions such as atherosclerosis and myocardial infarction [5]. Building upon a systematic analysis of the molecular network governing mitophagy and its role in CVDs, this review highlights the latest research trends in the field. In addition to confirming the roles of major vault protein (MVP) in counteracting atherosclerosis via the Parkin pathway and of mitochondrial calcium uniporter (MCU) dysfunction in causing calcium overload that disrupts mitophagy [6, 7], recent studies have uncovered novel regulatory mechanisms. These include : cardiolipin externalization mediated by Phospholipid Scramblase 3 (PLSCR3) [8], stabilization of PTEN-induced putative kinase 1 (PINK1) by the chaperone complex Heat shock protein 90 (HSP90) /Cell division cycle 37 (CDC37) [9], and the non-canonical function of complement regulatory protein CD55 in inhibiting the formation of the mitochondrial membrane attack complex [10]. Together, these findings significantly expand our understanding of mitophagy regulation. This review constructs a multidimensional regulatory network that extends beyond the conventional single-pathway perspective, elucidating the spatiotemporal heterogeneity across cardiovascular pathologies. We emphasize its dual role in different disease stages and cell types, advocating for interventions beyond simple activation/inhibition paradigms [11]. Additionally, it summarizes recent advances in therapeutic approaches targeting mitophagy (e.g., small-molecule activators, inhibitors, and gene editing technologies) and analyzes the key obstacles to their clinical application. Finally, we propose future research directions, emphasizing the development of tissue-specific regulatory tools, understanding disease heterogeneity, and constructing more reliable human models, thereby providing new insights for CVDs intervention [12]. 2. The molecular mechanism of mitophagy 2.1 Overview of the autophagy pathway Conventional macroautophagy is a central pathway for degrading cytoplasmic components (Fig.1). The process initiates with the activation of the Unc-51 like autophagy activating kinase 1 (ULK1) complex (ULK1-ATG13-FIP200-ATG101) in response to energy stress (e.g., mTOR inhibition) [13]. Subsequently, the Phosphatidylinositol 3-kinase (PI3K) complex (composed of VPS34, Beclin1, and ATG14) catalyzes the production of phosphatidylinositol 3-phosphate (PI3P), a lipid signaling molecule that guides phagophore nucleation [14]. During the elongation stage, the ATG5-ATG12-ATG16L1 ubiquitin-like (Ubl) conjugation system, facilitated by the E1/E2-like enzymes ATG7 and ATG3, drives the lipidation of Microtubule-associated protein 1A/1B-light chain 3 (LC3) (conversion from LC3-I to LC3-II), mediating phagophore expansion and substrate encapsulation [15]. The lipidated LC3-II is incorporated into the sealed double-membrane vesicle, forming the autophagosome, which is then transported along microtubules to the lysosome [16]. Finally, membrane fusion mediated by the SNAP receptor (SNARE) complex (STX17-SNAP29-VAMP8) forms the autolysosome, where the inner contents are degraded by hydrolytic enzymes [17].In this process, the ULK1 complex acts as the initiation hub, the PI3K complex regulates nucleation, and the ATG ubiquitin-like system drives membrane elongation. Furthermore, LC3 serves as both an autophagosomal marker and a key anchor point for selective autophagy receptors like BNIP3 [18]. 2.2 Specific mechanisms of mitophagy The clearance of damaged mitochondria relies on two highly coordinated molecular pathways: the PINK1-Parkin pathway (triggered by the loss of mitochondrial membrane potential) and the receptor-mediated pathway (which operates independently of Parkin). Upon the collapse of the mitochondrial membrane potential (ΔΨm) (Fig.2), the kinase PINK1 stabilizes and accumulates on the outer mitochondrial membrane (OMM) due to its impaired import through the translocase of Translocase of the outer/inner mitochondrial membrane (TOM/TIM) complex into the inner mitochondrial membrane (IMM) [19]. This process triggers PINK1 autophosphorylation at serine residues 228 and 104, leading to a fully active dimeric conformation. Activated PINK1 subsequently phosphorylates ubiquitin molecules (at Ser65) on the mitochondrial surface and the ubiquitin-like (Ubl) domain of Parkin (also at Ser65), thereby relieving Parkin’s autoinhibited state [20]. Upon activation, Parkin mediates the assembly of mixed ubiquitin chains (primarily linked through K6, K11, and K63). These chains subsequently modify proteins on the outer mitochondrial membrane (OMM), including Voltage-dependent anion-selective channel 1 (VDAC1) and Miro1/2. These ubiquitin modifications serve as molecular signals that recruit receptor complexes composed of OPTN, NDP52, and TAX1BP1. Specifically, OPTN recognizes ubiquitin chains via its UBAN domain, while NDP52 stabilizes the complex assembly through its SKICH domain. Together, these adaptors utilize conserved LC3-interacting region (LIR) motifs to bind LC3 and GABA type A receptor-associated protein (GABARAP) on the expanding phagophore, thereby anchoring the damaged mitochondrion to the nascent autophagosome for encapsulation [21, 22]. Receptor-mediated mitophagy is a key mechanism that operates independently of Parkin, in which mitochondrial receptor proteins directly recognize and recruit components of the autophagosome [23]. This process is primarily mediated by OMM proteins such as BNIP3, FUNDC1, BNIP3L, and Bcl2-L-13 [24]. These receptors contain an LIR that enables direct binding to LC3/GABARAP proteins on the autophagosomal membrane, thereby targeting damaged mitochondria for autophagic degradation [25]. BNIP3, whose expression is up-regulated under hypoxia, facilitates mitophagy through oligomerization and LIR-mediated interaction with LC3B, playing an especially important role in cardioprotection. FUNDC1 undergoes dephosphorylation under hypoxic conditions to enhance its affinity for LC3, and cooperates with core autophagy proteins such as Atg5, Atg7, and Atg12; its regulation involves crosstalk with pathways including those modulated by MARCH5. BNIP3L is primarily responsible for mitochondrial clearance during erythrocyte differentiation, while Bcl2-L-13 also participates in mitophagy through an LIR-dependent mechanism [26, 27]. Together, these pathways collectively ensure mitochondrial quality control and cellular homeostasis. This process is also precisely regulated by three auxiliary mechanisms (Fig.3) : First, mitochondrial damage activates the phospholipid scramblase PLSCR3, promoting the translocation of cardiolipin from IMM to OMM, where its tetra-acyl chains directly insert into hydrophobic pockets of LC3 [28]; Second, the molecular chaperone HSP90 forms a complex with CDC37 and stabilizes the kinase domain by binding to the N-terminal targeting sequence (amino acids 1–34) of PINK1 [29]; Third, the decay-accelerating factor DAF/CD55 inhibits the assembly of the C3 convertase, thereby reducing membrane attack complex (MAC)-mediated damage to the mitochondrial outer membrane and indirectly sustaining mitophagy efficiency [30].Together, these mechanisms form the molecular basis of mitochondrial quality control. 2.3 Mechanisms of mitophagic regulation The selective clearance of damaged mitochondria, known as mitophagy, entails a critically regulated process under the control of an intricate, multi-tiered network. This ensures that cells can promptly respond to mitochondrial damage and maintain homeostasis. The regulation operates at multiple core levels, ranging from transcriptional control to precise post-translational modifications of proteins. It also involves the perception and integration of diverse internal and external signals, such as cellular energy status (via AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR)), oxidative stress levels (via Reactive Oxygen Species (ROS) / Hypoxia-Inducible Factor (HIF)), and ionic homeostasis (particularly calcium). Together, these mechanisms enable cells to accurately and efficiently identify and eliminate impaired mitochondria, thereby ensuring metabolic homeostasis and cell survival (Table 1). Table 1: Multifaceted regulatory network of mitophagy Regulatory layer Key components/ pathways Molecular mechanism & role in mitophagy Ref. Transcriptional control peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) This master co-activator of mitochondrial biogenesis indirectly stimulates mitophagy by increasing the demand for the turnover of old or damaged organelles, thereby coupling biogenesis with quality control. [31] Transcription factor EB (TFEB) As a master regulator of lysosomal and autophagic genes, its activation transcriptionally upregulates key mitophagy receptors (e.g., BNIP3, BNIP3L) and lysosomal hydrolases, thereby enhancing the entire autophagic flux from initiation to degradation. [32] FoxO family These transcription factors are activated by cellular stress and promote the expression of a suite of autophagy-related genes, directly enabling the execution of selective mitophagic programs in response to metabolic and oxidative challenges [33] Post-translational modifications Phosphorylation Acts as a molecular switch for core machinery: it activates the ULK1 initiation complex, regulates the pro-autophagic VPS34 complex via Beclin 1, and controls the LC3-binding affinity of receptors like FUNDC1 to recruit autophagosomes. [34-36] Ubiquitination This modification is the cornerstone of the PINK1-Parkin pathway, wherein Parkin deposits ubiquitin chains on OMM proteins as ”eat-me” signals for autophagic adaptors like OPTN and NDP52, which then bridge the damaged mitochondrion to the forming autophagosome. [37] Others (acetylation, SUMOylation) Modifications such as acetylation and SUMOylation provide a secondary layer of control by fine-tuning the activity, stability, and interactions of key mitophagy proteins, adding complexity and specificity to the regulatory network. [38] Energy & Nutrient sensing AMPK As a cellular energy gauge (activated by AMP), it directly phosphorylates and activates mitophagy-initiating proteins like ULK1 while simultaneously suppressing the inhibitory mTORC1 pathway, thus promoting mitophagy under low-energy conditions. [39, 40] mTORC1 This nutrient-sensing complex inhibits mitophagy under nutrient-rich conditions by phosphorylating and inactivating key initiators like ULK1 and TFEB. Mitophagy is thus triggered upon mTORC1 inhibition during starvation or stress. [41, 42] Redox signaling ROS/ Hypoxia-inducible factor (HIF-1α) This axis senses oxidative stress: High ROS levels directly damage mitochondria and serve as activation signals, while stabilized HIF-1α under hypoxia transcriptionally induces the mitophagy receptors BNIP3 and BNIP3L, linking low oxygen and oxidative stress to mitochondrial clearance. [43, 44] Ionic signaling Ca²⁺ Calcium ions exert a dual influence: pathological Ca²⁺ overload triggers mitophagy by inducing mitochondrial membrane depolarization, while physiological Ca²⁺ fluxes can modulate the process through calcium-sensitive kinases that interface with core autophagy machinery. [45] 2.4 Lysosomal degradation The degradation of cytoplasmic components and subsequent material recycling in autophagy occur within the autolysosome—a structure formed by the fusion of the lysosome with the double-membraned autophagosome. Following its initiation in the cytoplasm, the autophagosome transports the cargo to this final degradative compartment. This vesicle specifically engulfs target materials for degradation, such as damaged organelles, misfolded proteins, and aggregates [46]. Following its formation, the autophagosome merges with the lysosome, forming an autolysosome [46]. This fusion process requires the participation of proteins including Rab7 and SNAREs to ensure precise docking and membrane fusion [47]. Inside the autolysosome, lysosomal hydrolases (including proteases, lipases, nucleases) degrade macromolecules into basic building blocks like amino acids, fatty acids, and sugars [48]. These molecules are subsequently transported back into the cytoplasm for reuse in biosynthesis, facilitating efficient nutrient recycling [49]. 3. The role of mitophagy in CVDs 3.1 Fundamental physiological functions Mitophagy is indispensable for maintaining functional homeostasis in cardiomyocytes, vascular endothelial cells, and smooth muscle cells. Its core physiological functions are primarily reflected in the following aspects. Clearance of damaged mitochondria Mitophagy selectively identifies and removes dysfunctional mitochondria, which is essential for cellular health [50]. Research from Kubli et al. (2013) provided direct evidence that the absence of Parkin led to exacerbated myocardial damage and heightened mortality in the context of myocardial infarction [51]. Promotion of mitochondrial turnover By eliminating damaged mitochondria, mitophagy creates space for the biogenesis of new organelles and facilitates the fusion and restructuring of healthy mitochondrial networks, ensuring optimal functionality [52]. Maintenance of energy supply Mitophagy ensures that cardiovascular cells meet their high and dynamic energy demands. Cardiomyocytes, among the most energy-dependent cells in the human body, rely heavily on a healthy and efficient mitochondrial network. Similarly, vascular endothelial and smooth muscle cells require a stable energy supply to perform their vascular functions [53]. 3.2 Consequences of dysregulation Dysregulated mitophagy—whether insufficient or excessive—disrupts cellular homeostasis and becomes a critical pathological factor in CVD progression [54]. Insufficient mitophagy (Deficiency) – damage accumulation and vicious cycle This is the most common and detrimental form of dysfunction in CVDs. The failure to clear damaged mitochondria triggers their accumulation, which sustains excessive ROS production. This initiates a self-perpetuating cycle of oxidative damage that spreads to previously healthy mitochondria, thereby compounding the initial injury [55]. Concurrently, the compromised mitochondrial pool results in significantly reduced cellular energy production efficiency [56]. More severely, mitochondrial components such as mitochondrial DNA (mtDNA), acting as damage-associated molecular patterns (DAMPs), persistently activate innate immune pathways (e.g., cGAS-STING), driving chronic low-grade inflammation. The synergistic effects of sustained oxidative stress, energy deficiency, and chronic inflammation ultimately contribute to extensive dysfunction and death (apoptosis or necrosis) across all major cardiac cell types [57]. Excessive mitophagy (overactivation) – energy depletion and damage Although less common, excessive mitophagy can occur in specific pathological contexts, such as the late phase of severe ischemia/reperfusion injury, or due to certain genetic or acquired regulatory abnormalities [58]. The core detriment lies in the non-selective over-removal of mitochondria, including those that are functional or only mildly impaired. This leads to a drastic reduction in healthy mitochondrial mass, resulting in a critical energy crisis (ATP depletion) [59]. Such excessive depletion of the mitochondrial network directly induces cellular dysfunction and may even trigger energy-dependent cell death (e.g., necrosis), contributing significantly to cardiovascular tissue damage [60]. 3.3 Role in specific CVDs Myocardial infarction (MI) In myocardial infarction, the role of mitophagy demonstrates distinct temporal dynamics [61]. In response to acute ischemia, a protective mitophagic response is swiftly mobilized. This involves concurrent PINK1-Parkin pathway activation and HIF-1α-induced BNIP3/BNIP3L expression, acting in concert to remove damaged mitochondria. This protective clearance process helps reduce the generation of ROS and inhibits cardiomyocyte apoptosis, thereby buying critical time for cell survival [62]. However, during the subsequent reperfusion phase, exacerbated calcium overload and oxidative stress may lead to hyperactivation of the same mitophagic pathways. This results in excessive depletion of the mitochondrial network and a severe energy crisis, ultimately expanding the infarct size and worsening myocardial injury. In the post-infarction remodeling phase, mitophagic function becomes relatively insufficient, failing to effectively remove the persistently accumulating damaged mitochondria. This failure sustains oxidative stress and inflammatory responses, driving pathological cardiac remodeling and contributing to the onset of heart failure [63]. Heart failure (HF) The function of mitophagy in patients with heart failure varies significantly depending on the phenotypic subtype [64] . In heart failure with reduced ejection fraction (HFrEF), the PINK1-Parkin pathway is often downregulated or functionally impaired, accompanied by dysregulation of BNIP3. This results in inadequate mitochondrial clearance, accumulation of damaged mitochondria, and subsequent energy crisis, oxidative stress, and chronic inflammation, which collectively promote cardiomyocyte death and fibrotic remodeling [65]. In contrast, in heart failure with preserved ejection fraction (HFpEF), mitophagy may be compensatorily activated in the context of metabolic inflammation, for instance through the FUNDC1 pathway. However, if this compensatory activation is sustained long-term and fails to restore mitochondrial homeostasis, it may lead to unstable energy supply and impaired myocardial contractile function [66]. Pathological cardiac hypertrophy Pathological cardiac hypertrophy is an adaptive response of the heart to chronic pressure overload, which can ultimately progress to heart failure [67]. The functionality of mitophagy undergoes dynamic alterations throughout this process [68]. During the early compensatory phase, mitophagy may be moderately activated to cope with increased stress and serve a protective role. However, as the disease advances to the late decompensatory stage, mitophagic activity becomes relatively insufficient due to the rate of mitochondrial damage exceeding clearance capacity, coupled with inhibitory signals such as mTOR activation [69]. Via ROS overproduction and NLRP3 inflammasome activation, the accumulated dysfunctional mitochondria promote cardiomyocyte apoptosis and widespread fibrosis. Notably, the forkhead box protein O3a (FOXO3a)–Parkin pathway negatively regulates cardiac hypertrophy by restoring mitophagic flux, revealing mitophagy as a potential therapeutic target in this pathology and its potential therapeutic value [70]. Atherosclerosis In atherosclerosis, impaired mitophagy is commonly observed across various vascular cell types. In endothelial cells, disturbed flow conditions suppress autophagic activity, initiating a cycle of mitochondrial damage accumulation and excessive ROS generation, thereby initiating endothelial dysfunction—an early critical step in atherogenesis [71]. In macrophages, oxidized low-density lipoprotein (ox-LDL) disrupts mitochondrial integrity and inhibits mitophagy, thereby facilitating a shift to the M1 macrophage phenotype and exacerbating inflammatory plaque progression through NLRP3 inflammasome activation. In vascular smooth muscle cells (VSMCs), impairment of mitophagy facilitates a transition to a synthetic phenotype, enhancing proliferation and migration, which contributes to plaque formation and compromises fibrous cap stability [72]. Diabetic cardiomyopathy Diabetic cardiomyopathy is a distinct form of myocardial remodeling specific to diabetic patients, closely associated with chronic hyperglycemia and lipotoxicity [73]. Elevated glucose levels and lipotoxic agents such as palmitate significantly suppress the function of both the PINK1-Parkin and FUNDC1 pathways, resulting markedly impaired mitophagy [74]. Impaired cardiac systolic and diastolic function ultimately arises from this substantial accumulation of damaged mitochondria, which promotes severe oxidative stress, lipid deposition, chronic inflammation (including cGAS–STING activation), and myocardial fibrosis [75]. Notably, Secreted Frizzled-Related Protein 2 (SFRP2) has been shown to ameliorate diabetic cardiomyopathy by activating mitophagy, highlighting the therapeutic potential of targeting mitophagic pathways in this condition [76]. Hypertension Hypertension is closely linked to mitophagy, which plays a critical role in hypertension-mediated organ damage (HMOD) [77]. The functional impact of mitophagy varies across different organ systems: in the heart, although mitophagy is compensatorily upregulated, this response remains insufficient to clear all damaged mitochondria, leading to their accumulation and accelerated myocardial remodeling [78]; in blood vessels, moderate mitophagic activity confers endothelial protection, suppresses abnormal smooth muscle proliferation, and delays vascular remodeling [79]; in the kidneys, timely enhancement of mitophagy helps alleviate mitochondrial dysfunction and slow the progression of renal injury [80]; and in the brain, precisely regulated mitophagy clears impaired mitochondria and effectively provides neuroprotection [81]. 4 Therapeutic strategies targeting mitophagy Functioning as a dedicated surveillance system, mitophagy preserves cellular homeostasis by selectively targeting and removing impaired mitochondria, especially in the cardiovascular system which has high energy demands. Targeting mitophagy represents a novel and attractive treatment avenue for a variety of CVDs. Current research emphasis has gradually shifted from basic mechanistic exploration to translational applications, aiming to develop clinically viable regulatory approaches. 4.1 Strategies to enhance mitophagy A variety of approaches can be employed to enhance mitophagy function, primarily including pharmacological activation, gene therapy, and lifestyle interventions. 4.1.1 Pharmacological activators Indirect activators These compounds indirectly enhance autophagic flux by modulating upstream signaling pathways. For example, AMPK activators (such as metformin and AICAR) promote ULK1 phosphorylation and initiate autophagy; Sirtuin 1 (SIRT1) activators upregulate autophagy-related gene expression via deacetylation mechanisms; mTOR inhibitors (such as rapamycin) alleviate their suppressive effect on autophagy, thereby broadly elevating cellular autophagic levels [82, 83]. Relatively specific target activators This category includes Urolithin A (which induces mitophagy and promotes mitochondrial biogenesis), spermidine (delaying cardiovascular aging through both autophagy-dependent and independent mechanisms), and Nicotinamide adenine dinucleotide (NAD⁺) precursors—the latter improving mitochondrial function via activation of the SIRT1/PGC-1α axis. In addition, small-molecule agonists targeting mitophagy receptors such as BNIP3, BNIP3L, or FUNDC1 are under active investigation [84-86]. Lysosomal function enhancers These agents act downstream in the autophagic cascade by facilitating autophagosome-lysosome fusion and degradation capacity. Examples include lysosomal pH modulators and function-promoting drugs (e.g., certain cathepsin agonists), which address impairments in fusion or degradative function [87]. 4.1.2 Gene therapy In specific genetic contexts or disease models, the overexpression of key mitophagy-related proteins—such as PINK1, Parkin, BNIP3, FUNDC1, and TFEB—using viral or non-viral delivery systems has demonstrated therapeutic potential. However, these approaches remain largely in the preclinical stage, with delivery efficiency and long-term safety representing major challenges. 4.1.3 Lifestyle interventions Caloric restriction and regular exercise are among the most translatable physiological strategies for enhancing mitophagy. Studies indicate that exercise promotes cardiac mitophagy and delays heart aging via the AMPK-FUNDC1 pathway, while intermittent fasting can significantly elevate autophagic activity, thereby improving metabolic health and cardiac function [88]. 4.2. Strategies to inhibit excessive mitophagy Although reduced mitophagy is observed in most CVDs, certain pathological conditions—such as septic cardiomyopathy, early ischemia-reperfusion injury, and specific neurodegenerative disorders—may involve excessive mitophagy, leading to cellular energy crisis and even apoptosis. Therefore, suppressing pathological mitophagy also holds therapeutic relevance [89]. Current research in this area remains preliminary. Potential strategies include developing small-molecule inhibitors of receptors such as BNIP3 or FUNDC1, modulating upstream Ca²⁺ signaling, or inhibiting hyperactivated mitochondrial fission processes [90]. 5 Issues and challenges Context-Dependent Dual Roles Mitophagy functions as a double-edged sword, exhibiting both protective and detrimental effects that vary by cell type and disease stage, necessitating precise regulation rather than simple enhancement or suppression. Technical Hurdles in Monitoring Reliable methods for real-time, quantitative monitoring of mitophagic flux in vivo are lacking, impeding a dynamic understanding of its physiological and pathological functions. Unclear Mechanisms of Non-Canonical Pathways The mechanisms of non-canonical mitophagy pathways, independent of PINK1-Parkin or known receptors, remain poorly understood, representing a significant knowledge gap. Insufficient Integration of Collaborative Networks How mitophagy is coordinated with other quality control mechanisms (e.g., biogenesis, fission/fusion) within an integrated regulatory network remains largely elusive. Lack of Clinically Applicable Modulators The most critical barrier is the severe shortage of clinically suitable drugs that combine high specificity, sufficient potency, and low toxicity for safe and effective therapeutic modulation. 6. Conclusion Mitophagy is a core mechanism for maintaining mitochondrial quality control and energy homeostasis in cardiovascular cells, with its functional status profoundly influencing cellular fate and disease progression. This review systematically elaborates on the critical roles of the PINK1-Parkin pathway and receptor-mediated pathways in cardiovascular diseases, underscoring the double-edged sword nature of mitophagy across different disease stages and cell types: appropriate activation clears damaged mitochondria and suppresses oxidative stress and inflammation, conferring protection; whereas either insufficient or excessive activity leads to toxic accumulation and energy depletion, respectively, thereby exacerbating tissue injury. 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Acknowledgements This work is supported by grants from the Fundamental Research Funds for the Central Universities (2042024YXA004), the National Natural Science Foundation of China (No. 82070410, 82270248), The Young Top-notch Talent Cultivation Program of Hubei Province, Knowledge Innovation Program of Wuhan-Basic Research. Declaration of Interest Statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Figure Legends Figure 1. Molecular Mechanism of Mitophagy: From Initiation to Lysosomal Degradation This schematic illustrates the key steps and molecular players involved in conventional macroautophagy, with a focus on mitophagy initiation and progression. The process is initiated by mTOR inhibition, which activates the ULK1 complex. The PI3K complex (VPS34–Beclin1–ATG14) is recruited by this complex, catalyzing the production of PI3P, which in turn promotes the nucleation of the phagophore membrane around damaged mitochondria. During elongation, the ATG5-ATG12-ATG16L1 conjugation system, facilitated by ATG7 and ATG3, catalyzes the lipidation of LC3 (conversion from LC3-I to LC3-II), promoting phagophore expansion and closure to form autophagosome. The autophagosome is then transported along microtubules to the lysosome. Finally, fusion mediated by the SNARE complex (STX17-SNAP29-VAMP8) results in the formation of the autolysosome, where hydrolytic enzymes degrade the engulfed mitochondrial cargo. LC3-II serves as both an autophagosomal marker and a docking site for selective autophagy receptors such as BNIP3. Figure 2. The PINK1-Parkin Pathway Orchestrates Mitophagy (A) Upon collapse of ΔΨm, PINK1 fails to be imported into the inner membrane via TOM-TIM complex and accumulates on OMM, where it undergoes autophosphorylation and activation. (B) Activated PINK1 phosphorylates Ub and the Ubl domain of Parkin at Ser65, relieving its autoinhibition and promoting Parkin recruitment to the OMM. (C) Activated Parkin, functioning as an E3 ubiquitin ligase, catalyzes the formation of ubiquitin chains (e.g., K6-, K11-, K63-linked) on OMM such as VDAC1. (D) Ubiquitin chains serve as binding platforms for autophagy adaptor proteins (OPTN, NDP52, TAX1BP1). These adaptors simultaneously bind LC3/GABARAP on the expanding phagophore via their LIR motifs, thereby anchoring the damaged mitochondrion for autophagosomal encapsulation. This figure is inspired by “Mitochondrial quality control in human health and disease”. Figure 3. Multifaceted Regulation of Mitophagy by PLSCR3, HSP90, and CD55 Mitochondrial damage activates the phospholipid scramblase PLSCR3, promoting cardiolipin translocation from IMM to OMM, where its tetra-acyl chains directly bind LC3 via hydrophobic interactions, facilitating phagophore recruitment. Simultaneously, the HSP90-CDC37 chaperone complex stabilizes PINK1 by binding to its N-terminal targeting sequence, ensuring proper kinase activation. Additionally, CD55 (DAF) inhibits C3 convertase assembly, preventing formation of MAC on the OMM, thereby protecting mitochondrial integrity and supporting efficient mitophagy. Together, these mechanisms fine-tune mitophagic signaling and maintain mitochondrial homeostasis. Information & Authors Information Version history V1 Version 1 20 November 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Xin-Yu Hu Wuhan University Renmin Hospital Department of Cardiology View all articles by this author Shu-Hong Zhao Wuhan University Renmin Hospital Department of Cardiology View all articles by this author Dan Huang Wuhan University Renmin Hospital Department of Cardiology View all articles by this author Shi-Ying Wang Wuhan University Renmin Hospital Department of Cardiology View all articles by this author Ying Xiong Wuhan University Renmin Hospital Department of Cardiology View all articles by this author Pan Wu Maternal and Child Health Hospital of Hubei Province View all articles by this author Hai-Jie Qi Wuhan Children’s Hospital Tongji Medical College Huazhong University of Science &Technology View all articles by this author Zhen-Guo Ma [email protected] Hubei Key Laboratory of Metabolic and Chronic Diseases View all articles by this author Metrics & Citations Metrics Article Usage 394 views 80 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Xin-Yu Hu, Shu-Hong Zhao, Dan Huang, et al. 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