The role of mitophagy in female reproductive system diseases: from molecular mechanisms to therapeutic strategies

The molecular mechanisms of mitophagy are broadly categorized into ubiquitin-dependent and ubiquitin-independent pathways ( 21 ). The prototypical ubiquitin-dependent pathway involves the PTEN-induced putative kinase 1 (PINK1)/PARK2 gene-encoded protein (Parkin) signaling cascade, which has emerged as a focal point in studies of mitophagy during female reproduction. Under physiological conditions ( 22 – 24 ), PINK1 is translocated to polarized mitochondria via the outer membrane translocase and inner membrane translocase complex. Upon crossing the inner mitochondrial membrane (IMM), PINK1 undergoes dual cleavage by the phosphoglycerate mutase family member 5-related rhomboid protease within the IMM. This generates an N-terminal fragment containing phenylalanine 104, which is retrotranslocated to the cytosol and subsequently degraded via the N-end rule pathway in a proteasome-dependent manner. This process ensures that PINK1 expression is maintained at low levels in healthy mitochondria. Under pathological conditions ( 25 – 28 ), particularly when cells are exposed to oxidative stress induced by reactive oxygen species (ROS) or other stressors, mitochondrial membrane depolarization prevents PINK1 from being imported into the mitochondria. As a result, PINK1 accumulates on the outer mitochondrial membrane (OMM) and undergoes autophosphorylation at serine 228. Activated PINK1 subsequently phosphorylates ubiquitin at serine 65, generating phosphorylated ubiquitin, which exhibits a high affinity for Parkin and recruits it from the cytoplasm to the mitochondrial surface. Subsequently, PINK1 directly or indirectly phosphorylates Parkin via phospho-Ser65-ubiquitin-mediated recruitment, exposing Parkin’s catalytic domain and triggering its E3 ubiquitin ligase activity. This leads to the formation of extensive ubiquitin chains on proteins on the OMM, serving as substrates for PINK1 and establishing a positive feedback loop that enhances Parkin recruitment and ubiquitination efficiency. Autophagy receptors such as optineurin (OPTN), nuclear dot protein 52 (NDP52), p62, BRCA1-associated protein 1 (NBR1), and TAX1-binding protein 1 (TAX1BP1), which possess ubiquitin-binding domains, recognize and bind to ubiquitinated proteins on damaged mitochondria ( 29 ). These receptors interact with Microtubule-Associated Protein 1 Light Chain 3 (LC3) positive autophagosomes, facilitating the selective engulfment and degradation of dysfunctional mitochondria. In contrast, the ubiquitin-independent pathway primarily relies on receptors that directly interact with LC3 or its homologs. Key mediators of this pathway include the Bcl-2 interacting protein 3-like (BNIP3L/Nix), Bcl-2 interacting protein 3 (BNIP3), and FUN14 domain-containing 1 (FUNDC1) pathways ( 30 , 31 ). BNIP3L, an OMM protein, mediates mitochondrial fission and mitosis ( 32 , 33 ) and directly interacts with LC3 on the autophagosomal membrane through its LC3-interacting region (LIR), promoting the engulfment of damaged mitochondria ( 34 , 35 ). BNIP3 works synergistically with Nix in recruiting Parkin and maintains mitochondrial homeostasis via the PINK1-Parkin pathway ( 36 ). FUNDC1, another outer membrane protein harboring an LIR domain, undergoes dephosphorylation at specific residues under hypoxic conditions, enhancing its affinity for LC3 and thereby promoting mitophagy ( 37 ). Besides, FUNDC1 synergizes with UNC-51-like kinase 1 (ULK1), leading to Ser17 phosphorylation and enhancing mitophagy activity ( 38 ).

In 1963, the Belgian cell biologist Christian de Duve coined the term “autophagy” to describe the cellular process wherein membrane-bound vesicles engulf cytoplasmic components. In the 1990s, Yoshinori Ohsumi and his team successfully identified key autophagy-related genes, and the subsequent cloning of the autophagy-related gene 1 marked a pivotal advancement in autophagy research. Following this breakthrough, the characterization of autophagy genes in mammals was achieved ( 1 – 3 ). Autophagy is a ubiquitous process in eukaryotic cells and can be categorized into macroautophagy, microautophagy, and chaperone-mediated autophagy, all of which play critical roles in maintaining cellular and tissue homeostasis. The form of autophagy primarily discussed in this review is macroautophagy. The discovery of the autophagy receptor sequestosome-1 (SQSTM1/P62) ( 4 ) established autophagy as a highly selective recycling mechanism. Depending on the specific molecules and subcellular components targeted for lysosomal degradation and recycling, autophagy can be further subdivided into specialized forms such as mitophagy, ribophagy, reticulophagy, and lipophagy ( 5 ). Mitochondria, as double-membrane-bound organelles ubiquitous in eukaryotic cells, are responsible for generating substantial amounts of adenosine triphosphate, which is essential for cellular energy metabolism. Moreover, mitochondria are involved in various critical cellular processes, including fatty acid synthesis, amino acid metabolism, calcium homeostasis, innate immune responses, and apoptosis regulation ( 6 ). Mitophagy represents a fundamental mechanism for preserving mitochondrial function and homeostasis by selectively targeting and degrading damaged mitochondria, thereby ensuring the integrity and quality of the mitochondrial population ( 7 – 9 ). In the context of the reproductive system, a sequence of highly coordinated molecular pathways govern sequential stages, encompassing gametogenesis, fertilization, pre-implantation embryo development, embryo implantation, and post-implantation development ( 10 ). As the primary energy providers for the ovaries and uterus, mitochondria and their associated autophagic mechanisms are vital to these processes. An increasing body of evidence ( 11 – 13 ) suggests that the mitophagy pathway is intricately involved in key reproductive physiological processes, such as follicular development, fertilization, and implantation, and is closely linked to the pathogenesis of various female reproductive disorders, including endometriosis, polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), and ovarian aging (OA). This review systematically summarizes and critically evaluates the current body of research. Furthermore, existing therapeutic strategies targeting mitophagy are classified, the current state of research progress is discussed, and potential future directions are proposed. This comprehensive approach aims to provide novel insights into the treatment of diseases affecting the female reproductive system while improving reproductive health outcomes in women.

In addition to the aforementioned strategies, both molecular compounds and TCM have shown considerable promise for enhancing female reproductive function. Key molecular compounds include melatonin, zinc, spermine, and prostaglandin F2α (PGF2α). Current evidence suggests that melatonin modulates granulosa cell function through activation of the mitophagy pathway, specifically by mitigating oxidative stress-induced damage and apoptosis. Zinc and spermine exert beneficial effects on oocyte mitochondrial function through distinct regulatory mechanisms: zinc suppresses excessive mitophagy activation, whereas spermine promotes mitophagy activity, ultimately contributing to improved oocyte quality. PGF2α plays a crucial role in initiating luteolysis by activating mitophagy during the early phase of corpus luteum regression, which may help ameliorate luteal insufficiency in women. In the context of TCM, ginsenoside Rg1 and salidroside have been demonstrated to enhance mitochondrial function in oocytes and improve overall reproductive capacity. Melatonin (N-acetyl-5-methoxytryptamine) is a compound secreted in the ovary, composed of indoleamine and acetyl groups. Its receptors, MT1 and MT2, are highly expressed in GCs, thereby enhancing cellular communication between GCs and melatonin. This not only supports the physiological functions of GCs but also amplifies melatonin’s regulatory effects on GCs ( 115 – 117 ) Several studies ( 118 , 119 ) have confirmed that during female reproduction, melatonin mitigates oxidative damage in GCs, reduces cell apoptosis, and promotes oocyte maturation. Xu et al. ( 120 ) proposed that melatonin regulates GCs via mitophagy. Specifically, melatonin upregulates the expression of PINK1, Parkin, BECLIN1, and LC3II/LC3I in bovine GCs, activating PINK1-Parkin-mediated mitophagy and enhancing reproductive capacity. The activation of mitophagy by melatonin relies on the SIRT1-FoxO1 signaling pathway. More precisely, melatonin interacts with NAD+-dependent histone deacetylase SIRT1, which deacetylates FoxO1 and inhibits its activity ( 121 , 122 ), thereby reducing the transcriptional activity of pro-apoptotic factors mediated by FoxO1, decreasing GC apoptosis, and improving follicular development ( 123 ). In the context of PCOS, mitophagy exhibits protective effects on GCs through diverse regulatory mechanisms ( 124 ). In KNG cells, mice, and PCOS patients, melatonin significantly increases SIRT1 expression, suppresses excessive activation of the PINK1-Parkin pathway, restores mitochondrial function, and alleviates GC damage caused by PCOS, thereby improving both in vivo and in vitro phenotypes of PCOS. Therefore, further investigation into the mechanism of melatonin’s effects on GCs through mitophagy in various cellular environments is warranted. Research ( 125 , 126 ) on porcine oocytes has demonstrated that excessive activation of PINK1-Parkin-mediated mitophagy can lead to zinc deficiency. Zinc is an essential trace element that plays a critical role in numerous cellular physiological processes, including transcription, protein synthesis, enzyme activity, cell division, growth, and transport. In the female reproductive system, zinc deficiency inhibits the synthesis and activity of copper-zinc SOD2, increases the acetylation level of SOD2, and enhances cellular sensitivity to ROS, thereby triggering oxidative stress and early apoptosis in oocytes. These cellular events impair meiotic progression, disrupt cytoskeletal integrity, and cause mitochondrial dysfunction, ultimately reducing oocyte quality. Therefore, zinc supplementation may serve to inhibit hyperactivated mitophagy, alleviate oxidative stress, restore mitochondrial function in oocytes, and thereby maintain intracellular homeostasis within oocytes. Selenium is an essential trace element for female reproductive health. It is predominantly localized in the granulosa cell layer and highly expressed in large, healthy follicles, where it may serve as an antioxidant during the later stages of follicular development ( 127 ). Given the bidirectional regulatory relationship between mitophagy and oxidative stress, it is essential to investigate the involvement of mitophagy in selenium-mediated regulation of the female reproductive system. Furthermore, Zhang et al. ( 83 ) confirmed through non-targeted metabolomics technology that spermidine, a polyamine metabolite, is a key metabolite in the ovary. Increasing the level of spermidine in the ovaries of aged mice promoted follicular development, oocyte maturation, and early embryo development. Microtranscriptomic studies further revealed that this improvement in oocyte quality was achieved through activation of mitophagy and mitochondrial function mediation, and this mechanism remains active under oxidative stress conditions in porcine oocytes. In summary, regulating the mitophagy pathway effectively enhances oocyte quality. Luteolysis is a pivotal regulatory mechanism in the female reproductive cycle. Bennegard et al. ( 128 ) suggested that elucidating the cellular events occurring during early luteolysis could be an important strategy for improving female fertility. Auletta et al. demonstrated that increasing PGF2α levels in the rhesus monkey luteum could induce luteolysis ( 129 ). Similarly, Plewes et al. observed this phenomenon in bovine luteum ( 130 ). During the early stages of luteolysis, PGF2α activates PINK1 and stimulates Parkin phosphorylation. This finding suggests that mitophagy and mitochondrial fission are involved in the early cellular activities of luteolysis. Although the PGF2α analogues used in these studies do not fully replicate the PGF2α secreted by the uterus, and physiological luteolysis involves more complex mechanisms than PGF2α signaling alone, this research highlights the potential of mitophagy as a therapeutic target for luteal insufficiency. The aforementioned therapeutic approaches targeting mitophagy have shown promising effects on granulosa cell damage, oocyte quality defects, and luteal insufficiency. Thus, mitophagy holds significant potential as a therapeutic target for enhancing female reproductive capacity. Ginseng, a perennial herb belonging to the genus Panax in the family Araliaceae, contains ginsenoside Rg1 as its primary bioactive constituent. Ginsenoside Rg1 is a tetracyclic triterpene saponin that has demonstrated protective effects against oxidative stress-induced damage in various pathological conditions, including diabetes, ischemic stroke, and depression ( 131 – 133 ). In diabetic rat models, ginsenoside Rg1 significantly elevated superoxide dismutase (SOD) levels. In both in vivo and in vitro models of ischemic stroke, ginsenoside Rg1 activated the Nrf2/ARE signaling pathway, thereby enhancing the cellular antioxidant defense system. Furthermore, ginsenoside Rg1 was shown to downregulate the expression of NADPH oxidase isoforms NOX1 and NOX4 in the hippocampus of depression-induced rats, thereby alleviating oxidative stress. As previously discussed, a bidirectional regulatory relationship exists between oxidative stress and mitophagy. Ginsenoside Rg1 has also been reported to improve fertility in ovarian aging mouse models by increasing antioxidant enzyme levels, suggesting its potential regulatory role in the female reproductive system via mitophagy modulation ( 134 ). A study by Yang et al. ( 84 ) established an oxidative stress-induced OA model in Drosophila using tert-butyl hydroperoxide and demonstrated that ginsenoside Rg1 treatment induced PINK1-mediated mitophagy, thereby reducing oxidative damage and improving reproductive capacity. Molecular docking analysis further revealed that Rg1 exhibited strong binding affinity with the active domain of PINK1 and formed hydrogen bonds. These findings suggest that ginsenoside Rg1 may exert its therapeutic effects in OA by activating the PINK1-mediated mitophagy pathway in ovarian cells, promoting mitochondrial degradation, reducing excessive ROS accumulation, and alleviating redox imbalance caused by decreased SOD2 and catalase activity, ultimately reversing oxidative stress-induced reproductive damage. Recent studies have indicated that salidroside (2-(4-hydroxyphenyl)ethyl-β-D-glucopyranoside), the primary bioactive compound extracted from the roots and rhizomes of Rhodiola rosea , exhibits therapeutic potential in the treatment of premature ovarian aging. In an experimental study on porcine oocytes ( 135 ), salidroside significantly reduced ROS levels, enhanced MMP and ATP production, increased mitochondrial DNA copy number, and promoted both cytoplasmic and nuclear maturation of oocytes. In subsequent embryo development, salidroside-treated embryos exhibited increased blastomere counts, improved blastocyst proliferation, and upregulated expression of pluripotency genes. Moreover, mitochondrial-targeted molecules have been shown to ameliorate spindle and chromosome abnormalities in aged mouse and human oocytes, suggesting that mitochondrial dysfunction plays a central role in the pathogenesis of ovarian aging ( 136 ). Therefore, the therapeutic effects of salidroside on OA are closely associated with mitophagy regulation. A recent study ( 85 ) confirmed through transcriptomic and microproteomic analyses that salidroside could maintain normal spindle and chromosome alignment and preserve mitochondrial membrane potential via mitophagy activation, thereby enhancing oocyte maturation, fertilization capacity, and embryonic developmental potential in OA mouse models. Both ginsenoside Rg1 and salidroside are bioactive constituents of TCM, which are characterized by their multi-target and multi-pathway regulatory properties. Salidroside, for instance, interacts with key molecular targets such as Tumor Necrosis Factor-alpha, Interleukin-2, Bcl-2, Cyclooxygenase-2, Vascular Endothelial Growth Factor, cysteine-aspartic acid protease 3, and Hypoxia-Inducible Factor-1alpha, and modulates multiple signaling pathways including PI3K/Akt/mTOR, Mitogen-Activated Protein Kinases, Extracellular Signal-Regulated Kinase 1 and 2, Glycogen Synthase Kinase-3 Beta, and Nuclear Factor Erythroid 2-Related Factor 2. These molecular targets and pathways are closely associated with the pathophysiological mechanisms of female reproductive disorders, underscoring the therapeutic potential of salidroside in reproductive medicine. Despite its promising effects, there remains a lack of comprehensive long-term toxicological data to support its clinical application. However, existing toxicity studies have not identified significant adverse effects. Besides, the bioavailability of salidroside is closely related to its synthetic methodology. Therefore, optimizing the synthesis and derivatization of salidroside represents a promising avenue for advancing its clinical application in TCM ( 137 ).

Mitophagy is closely associated with the onset and progression of diseases affecting the female reproductive system, including endometriosis, PCOS, POI, and OA ( Table 1 ). In the context of endometriosis, mitophagy plays a regulatory role in the apoptosis and migration of endometrial stromal cells, thereby suppressing the formation of ectopic implantation lesions. Regarding PCOS, mitophagy primarily affects ovarian granulosa cells. Excessive activation of mitophagy may impair granulosa cell function, as evidenced by reduced expression of MMPs and mtDNA. The administration of Reverse Erythroblastosis Virus Oncogene Homolog (REV-ERB) has been shown to ameliorate such cellular dysfunction. Furthermore, iron-dependent mitophagy operates under varying oxidative conditions within granulosa cells, contributing to improved follicular development. The role of mitophagy in POI is complex. Notably, increased levels of autophagosomes and autolysosomes have been observed in granulosa cells of POI mouse models, along with elevated expression of mitophagy-related proteins in ovarian tissues compared to normal controls. Conversely, some studies have suggested that enhanced mitophagy activity may promote follicular development and regulate sex hormone levels, thereby improving ovarian function; however, the underlying mechanisms require further investigation. Finally, in OA, mitophagy primarily influences the meiotic progression of germinal vesicle-stage oocytes, helping to correct maturation defects. Suppression of hyperactivated mitophagy has been shown to enhance oocyte quality in OA. Mitophagy and reproductive disorders. Endometriosis is a chronic, hormone-dependent inflammatory disorder characterized by the ectopic implantation of endometrial glands and stroma outside the uterine cavity. It has been established as one of the leading causes of pelvic pain, dysmenorrhea, and infertility, affecting approximately 5% to 10% of women of reproductive age ( 86 , 87 ). Accumulating evidence indicates that the interplay among apoptosis, angiogenesis, autophagy, and mitophagy plays a complex role in the pathogenesis of endometriosis in rodent models ( 88 ). PINK1 serves as a key initiator of mitophagy. In rat models of endometriosis ( 70 ), the PINK1-Parkin-mediated mitophagy pathway suppresses cell proliferation, migration, and invasion through upregulation of prohibitin 2. Furthermore, the PINK1-Parkin mitophagy pathway represents a critical mechanism by which macrophage stimulator 1 (Mst1), a negative regulator of endometriosis, modulates apoptosis and migration in human endometrial stromal cells (ESCs) ( 89 ). Mst1 inhibits Parkin transcription and expression, thereby suppressing mitophagy and promoting ESC apoptosis while restricting cell migration. Specifically, Mst1 overexpression leads to reduced Parkin expression, mitochondrial fragmentation, impaired lysosomal co-localization, cytoplasmic calcium overload, and decreased F-actin expression. Besides, the coordinated regulation of mitophagy and apoptosis via the PINK1-Parkin pathway has been associated with the mTOR signaling cascade ( 90 , 91 ). Both autophagy and PINK1-Parkin-mediated mitophagy activate the mTOR pathway, which in turn stimulates pro-apoptotic Bcl-2 family proteins on the mitochondrial membrane, ultimately inducing apoptosis through calcium channel blockers. Endometrial cell apoptosis can counteract angiogenesis to some extent, thereby reducing the volume, area, and diameter of endometriotic lesions and impeding disease progression. The mitochondrial quality control system in endometriosis has been closely linked to REV-ERB. Brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) are core components of the circadian clock machinery. REV-ERB forms a feedback regulatory loop with downstream target genes, directly influencing mitochondrial quality control and sleep-wake patterns ( 71 ). The chronic estrogen dependence of endometriosis may further contribute to sleep disturbances. Modulating circadian rhythms and restoring mitochondrial function may offer therapeutic potential for endometriosis. Although direct evidence linking mitophagy to circadian regulation remains limited, mitochondrial fission and fusion, processes closely associated with mitophagy, exhibit circadian oscillations synchronized with the light/dark cycle through the phosphorylation-dependent activation and inactivation of DRP1 ( 92 ). These findings suggest that mitophagy may play a role in the regulation of circadian rhythms and the progression of endometriosis. PCOS is the most prevalent endocrine disorder in women of reproductive age, with major characteristics encompassing ovulation dysfunction, hyperandrogenism and polycystic ovarian morphology. One in six women of reproductive age is afflicted by PCOS, which constitutes the primary cause of subfertility ( 93 , 94 ). The pathogenesis of PCOS is closely linked to mitochondrial energy metabolism ( 95 ). Studies have shown that in human ovarian granulosa cells (KNG) treated with dihydrotestosterone, the MMP and mtDNA content were reduced, whereas the abundance of autophagosomes and the levels of key mitophagy proteins PINK1 and Parkin were elevated. This suggests that excessive activation of mitophagy contributes to GC damage. Comparable alterations were detected in the GCs of individuals diagnosed with PCOS. In addition, the study by Zhao et al. revealed that in the GCs of patients with PCOS, in addition to the previously mentioned alterations, the mitophagy receptors Nix and RHEB were also highly expressed. This finding provides further evidence of the involvement of mitophagy in granulosa cell dysfunction in PCOS. Dysfunctional GCs can induce oxidative stress and chronic inflammation, consistent with the pathophysiological mechanisms underlying PCOS ( 96 , 97 ). Future studies should aim to directly validate this targeted relationship, thereby facilitating potential clinical translation. REV-ERB serves as a central regulator of the circadian clock and is intricately linked to mitochondrial biosynthetic functions ( 98 ). REV-ERB inhibits the translocation of Park2, a key factor in mitophagy, to mitochondria or modulates the activity of the mitophagy activator ULK1, thereby maintaining mitochondrial structure and function ( 72 ). In PCOS patients, REV-ERB expression is significantly reduced in GCs ( 73 ). A study by Amador et al. found that treating PCOS mice with SR9009, a REV-ERB agonist, suppressed over-activated mitophagy. This upregulated the expression of peroxisome proliferator-activated receptor γ coactivator 1α, nuclear respiratory factor 1, and mitochondrial transcription factor A, genes associated with mitochondrial biogenesis. The enhanced expression of these genes promoted mitochondrial biogenesis, corrected quality defects in GCs caused by PCOS, and facilitated follicular development and maturation, thereby regulating female reproductive capacity. Iron-mediated mitophagy plays a critical role in the pathogenesis of PCOS. Ammonium ferric citrate activates transferrin receptor 1 (TFRC), thereby increasing intracellular iron levels, which leads to the accumulation and release of ROS, overactivation of the PINK1-dependent mitophagy pathway, induction of ferroptosis, and inhibition of follicular development via the TFRC/NOX1/PINK1/ACSL4 signaling axis. Therefore, reducing iron uptake may facilitate normal follicular development in PCOS. Zhang et al. ( 74 ) consistently reported that activation of ACSL4 in KNG cells suppressed normal follicular development, with abnormal follicle formation being closely associated with the initiation and progression of PCOS ( 99 ). The regulatory mechanism of mitophagy is influenced by the cellular redox status. CDGSH iron-sulfur domain 2 (CISD2), a protein found on the outer mitochondrial membrane, endoplasmic reticulum, and mitochondria-associated membranes, functions as a [2Fe-2S] cluster-containing protein with oxygen-reducing activity, and participates in the regulation of cellular iron metabolism, ROS homeostasis, and mitophagy ( 100 – 103 ). The involvement of CISD2 in electron and iron-sulfur cluster transfer defines its functional relationship with mitophagy. Under reducing conditions, CISD2 is unable to transfer [2Fe-2S] clusters; however, under oxidative stress, CISD2 facilitates iron transport into the mitochondrial matrix and transfers electrons to oxygen through oxidized NAD+ (an electron donor), thereby promoting oxidative stress and generating superoxide radicals (O 2 − ) ( 104 – 106 ). Wu et al. ( 75 ) established a PCOS model in KNG cells using testosterone and observed elevated CISD2 expression under oxidative conditions. Silencing CISD2 expression via shRNA significantly enhanced PINK1-Parkin-mediated mitophagy and upregulated SOD2 expression, thereby attenuating oxidative stress and stabilizing the follicular microenvironment. Besides, studies have explored PCOS-related clinical features such as insulin resistance and obesity. In obese humans and rats, the expression levels of mitophagy-related molecules, including Parkin, FUNDC1, and BNIP3, are markedly decreased. These mitophagy defects impair the metabolic differentiation of adipose tissue, contributing to insulin resistance ( 76 – 78 ). Therefore, mitophagy may alleviate PCOS symptoms by modulating metabolic pathways, offering valuable insights for developing clinical strategies. POI, characterized by the premature depletion of ovarian follicles before the age of 40, is a major contributor to female infertility ( 107 ). Mitophagy plays a critical role in maintaining ovarian function by mitigating excessive ROS accumulation and preventing mtDNA damage. However, excessive activation of mitophagy may contribute to the development of POI. Miao et al. demonstrated that in POI mice, the expression levels of PINK1 and Parkin were elevated in the ovaries, accompanied by an increased number of autophagosomes and autolysosomes in GCs, suggesting that excessive mitophagy is involved in the pathogenesis of POI ( 108 ). A cohort study involving 375 patients identified mitophagy as a potential therapeutic target for POI ( 109 ). Sequencing analysis revealed a homozygous single-nucleotide insertion in exon 1 of the SPATA33 gene ( NM_153025.2 : c.34dup; p.Cys12LeufsTer2). SPATA33, a protein exclusively expressed in mitochondrial germ cells, has been recognized as a novel mediator of mitophagy ( 110 ), providing genetic evidence linking POI with mitophagy. There are varying perspectives on the precise relationship between mitophagy and the pathogenesis of POI. Some studies have indicated that the pathological process of POI is closely associated with the suppression of the PINK1-Parkin pathway ( 111 , 112 ). Yao et al. overexpressed neurotrophin-induced gene B (Nur77) in the ovaries of POI mice. Nur77, a member of the nuclear hormone receptor NR4A family, regulates pathological processes such as metabolic abnormalities, hypoxia stress, and inflammation. Activation of Nur77 can induce PINK1-Parkin pathway-mediated mitophagy, thereby improving follicular development and sex hormone levels in POI mice and enhancing ovarian function. However, this study lacked a control group with inhibited mitophagy and did not include recovery experiments following Nur77 overexpression ( 79 ). Compared to other reproductive disorders, research on POI is extensive and diverse, offering multiple perspectives for future investigations and aiding in the elucidation of the precise mechanisms of mitophagy’s involvement. OA is defined as the progressive decline and ultimate exhaustion of ovarian function, marked by a reduction in follicle abundance and deterioration in oocyte quality ( 13 ). Furthermore, compromised oocyte quality is strongly associated with adverse reproductive outcomes, such as fertilization failure, impaired embryo development, and miscarriage. Wang et al. demonstrated that excessive activation of mitophagy mediated by the PINK1-Parkin pathway plays a critical role in the physiological mechanisms underlying OA, particularly in germinal vesicle-stage oocytes ( 113 ). Pan et al. proposed that both mitophagy and mitochondrial trafficking contribute to OA. Specifically, Parkin, lysosome-associated membrane protein 2, and mitochondrial dynamics-related protein 1 worked synergistically with mitochondrial Rho-GTPase, an OMM protein, to regulate mitochondrial transport and mitophagy during oocyte meiosis, thereby alleviating maturation defects in OA oocytes ( 114 ). Jin et al. further revealed that mitophagy exerts regulatory effects during this process. Notably, RAB7, a key regulator of the late endosome/lysosome network, remains active during meiosis to suppress excessive PINK1-Parkin-mediated mitophagy, thus enhancing oocyte quality in the context of OA ( 80 ). Besides, endogenous C-type natriuretic peptide (CNP), secreted by GCs in the follicular wall, mitigates DNA damage and apoptosis in OA oocytes, ensuring adequate time for cytoplasmic maturation ( 81 , 82 ). This effect is primarily achieved through CNP destabilizing PINK1 and inhibiting Parkin recruitment, thereby restoring mitochondrial oxidative phosphorylation. The therapeutic potential of compounds like spermidine and traditional Chinese medicine for OA will be discussed in more detail later.

Mitophagy represents a critical mechanism for mitochondrial quality control, with most current research centered on the PINK1/Parkin signaling pathway. Within the context of female reproductive physiology, mitophagy exerts essential regulatory functions in follicular development and fertilization. Notably, it demonstrates bidirectional regulatory properties during follicular atresia, a phenomenon that is also evident in the pathogenesis and therapeutic strategies of reproductive disorders. The bidirectional regulation is primarily governed by the intracellular redox status. Future investigations should aim to elucidate the biological thresholds that determine mitophagy activation and suppression, as well as the tissue- and cell-specific variations, which may facilitate the development of precise regulatory interventions for female reproductive diseases. Research on mitophagy’s role during embryo implantation and post-implantation development remains limited and primarily indirect. Nevertheless, this area holds significant potential for improving female pregnancy outcomes and advancing assisted reproductive technologies, warranting further in-depth exploration. In the pathological context of the female reproductive system, mitophagy has been implicated in the progression of endometriosis, PCOS, premature ovarian insufficiency, and ovarian aging. Studies on the regulatory mechanisms of mitophagy have revealed that it not only collaborates with key mitochondrial quality control pathways, including mitochondrial biogenesis, fission/fusion dynamics, and transport, but also interacts with the mitochondrial unfolded protein response (UPRmt), ferroptosis signaling, and apoptotic cascades. The complex interplay between mitophagy and apoptosis is particularly notable across multiple biological levels and processes. During follicular atresia, mitophagy suppresses granulosa cell apoptosis and sustains cellular viability. In endometriosis, it modulates the apoptotic and migratory behaviors of endometrial stromal cells, thereby mitigating lesion progression. In PCOS, inhibition of the PINK1/Parkin pathway reduces oocyte apoptosis and enhances oocyte quality. Besides, melatonin and zinc have been shown to enhance reproductive function by mitigating granulosa and oocyte apoptosis via mitophagy induction. Emerging evidence further suggests that epigenetic mechanisms may directly regulate the mitochondrial quality control network, implying a potential targeted interaction between epigenetic modifications and mitophagy ( 138 ). However, the underlying mechanisms linking these processes in the context of reproductive biology remain to be fully elucidated. Collectively, these findings expand our understanding of the molecular regulatory networks involving mitophagy and underscore its therapeutic potential in the prevention and treatment of female reproductive disorders. Beyond well-characterized compounds such as melatonin, zinc, spermidine, and prostaglandin F2α, bioactive constituents of traditional Chinese medicine, such as ginsenoside Rg1 and salidroside, have demonstrated the capacity to enhance female reproductive function through the modulation of mitophagy. The principal mechanism involves the mitigation of ROS-induced cellular damage. However, current studies on mitophagy in relation to traditional Chinese medicine remain limited in both scope and methodological rigor. Future research should focus on delineating the interplay between mitophagy and multiple molecular signaling pathways, while refining experimental designs to identify and validate specific therapeutic targets. To date, most investigations into mitophagy have been conducted using in vitro cell models or in vivo animal systems. Advances in high-throughput sequencing technologies and machine learning methodologies offer novel opportunities to integrate multi-omics approaches, identify key regulatory mitophagy factors, and validate their functional roles across experimental platforms, including in vivo , in vitro , and clinical settings. These developments are critical for establishing the clinical relevance of mitophagy in the diagnosis and therapeutic management of female reproductive disorders.

Mitochondrial quality control involves maintaining the dynamic balance of mitochondrial fission and fusion, repairing mitochondrial DNA (mtDNA) mutations, and executing its core mechanism, mitophagy, to ensure the functional integrity of the mitochondrial network ( 14 ). Mitochondrial dysfunction may occur during cellular differentiation, hypoxic responses, or paternal mtDNA elimination after fertilization. Upon detecting mitochondrial damage, cells regulate mitochondrial distribution and morphology through fusion and fission while activating the mitochondrial unfolded protein response (UPRmt) to address the accumulation of misfolded proteins and restore intracellular homeostasis. However, when these mechanisms fail to adequately restore mitochondrial function, mitophagy selectively targets and degrades damaged mitochondria, thereby preserving mitochondrial quality and maintaining cellular homeostasis ( 15 – 18 ). The process of mitophagy, from its initiation to the clearance of dysfunctional mitochondria, can be divided into four steps ( 19 ): 1) A significant loss of mitochondrial membrane potential (MMP/ΔΨm) in the damaged mitochondria. 2) Complete engulfment of mitochondria by autophagosomes, forming mitophagosomes. 3) Fusion of mitophagosomes with lysosomes. 4) Formation of autolysosomes or translocation of lysosomal acid hydrolases into autophagosomes for the degradation of damaged mitochondria. Concurrently, new proteins and lipids are synthesized and integrated into the existing mitochondrial network. With a few exceptions, such as the development of mature lens fiber cells in vertebrates ( 20 ), mitophagy and mitochondrial biogenesis are two opposing yet complementary processes that synergistically mediate mitochondrial renewal at multiple levels to restore mitochondrial function.