Aberrant mitochondria in endometriosis: From pathogenic mechanisms to therapeutic opportunities

In recent years, researchers have increasingly acknowledged the significant role of mitochondrial dysfunction in endometriosis and investigated its potential as a clinical biomarker and therapeutic targets ( Figure 3 ). Figure 3 Clinical implications of targeting mitochondrial function in endometriosis Created in BioRender. Rong, Y. ( https://BioRender.com/dmwaw1s ) is licensed under CC BY 4.0. Clinical implications of targeting mitochondrial function in endometriosis Created in BioRender. Rong, Y. ( https://BioRender.com/dmwaw1s ) is licensed under CC BY 4.0. The diagnosis of endometriosis has consistently posed a challenging clinical issue: it is sometimes delayed for years and is susceptible to mistake, and treatment is often postponed; precise clinical diagnosis is crucial for prompt intervention. 104 Conventional diagnostic techniques predominantly depend on imaging and laparoscopic surgery; nonetheless, these approaches possess constraints and inherent invasiveness. In recent years, blood tests utilizing mitochondrial biomarkers (detected in plasma or serum samples) have been acknowledged for their considerable clinical potential to offer a more precise and straightforward diagnostic method. 83 Each cell generally contains tens to hundreds of copies of mtDNA, while the nuclear genome typically has only one or two copies. The mutation rate of mtDNA is 10–17 times greater than that of nuclear DNA, and these mutations can be identified early in the disease’s pathogenesis (in circulating cell-free DNA from plasma). 105 J. Creed et al. documented the clinical utilization of mitochondrial genome mutations in plasma for the identification of probable endometriosis, particularly in female patients exhibiting related symptoms. 106 Furthermore, the assessment of alterations in mtDNA copy number and mutations in oocytes or follicular fluid may serve as an indicator of the risk for developing endometriosis, whereas a reduction in mtDNA copy number in these samples could signify compromised mitochondrial function, thereby impacting oocyte quality and pregnancy outcomes. 107 Mitochondrial indications are anticipated to facilitate the early detection of endometriosis and may also assist in disease staging and prognosis in near future. Given the pivotal role of mitochondrial dysfunction in the pathogenesis of endometriosis-associated pain and infertility, targeting mitochondria represents a rational therapeutic direction ( Table 2 ). Aberrant mitochondrial metabolism, OS, and impaired bioenergetics not only contribute to lesion survival and progression but also influence nociceptive signaling and oocyte competence. Several bioactive compounds and pharmacological agents have shown potential to modulate mitochondrial function, thereby alleviating pain, improving fertility outcomes, or both. Preclinical studies in animal models and patient-derived cell models indicate that such interventions can achieve dual benefits by attenuating pain while enhancing reproductive capacity, highlighting mitochondria-centric therapy as a promising adjunct or alternative to current hormone-based regimens. Table 2 Mitochondria-targeted therapies and their effects on pain and infertility in endometriosis Category Mechanism/compound Validation model Main action on mitochondria & metabolism Special effect on pain Special effect on infertility Reference Antioxidants MDHB Mouse endometriosis model (peritoneal implantation), human ovarian granulosa cells Restores ΔΨm, increases ATP, upregulates Nrf2/SOD1/NQO1/GCLC Not reported Improves oocyte and embryo quality via reduced oxidative stress Li et al., 107 Park et al. 108 Vanillin Mouse endometriosis model (peritoneal implantation) Antioxidant, reduces ROS in lesions, inhibits complex IV Potential analgesic effect via ROS reduction Not reported Liu et al. 109 Naringenin Mouse endometriosis model (peritoneal implantation) Lowers mitochondrial potential, induces apoptosis, upregulates Nrf2/HO-1, downregulates KEAP1 Potential analgesic effect through anti-inflammatory/ROS modulation Not reported Kapoor et al. 68 Vitamin D or ω-3 fatty acids Clinical randomized controlled trial (adolescent girls and young women with endometriosis) Potential pain relief via anti-inflammatory action Potential pain relief via anti-inflammatory action Potential fertility preservation through improved metabolic and inflammatory status Nodler et al. 26 Vitamin C and vitamin E supplementation Clinical randomized controlled trial (women with endometriosis) Reduces oxidative stress markers Pain reduction observed in clinical trial Potential fertility preservation via oxidative stress reduction Amini et al. 27 Vitamin D supplementation Clinical randomized controlled trial (women with endometriosis) Improves clinical symptoms and metabolic profiles Symptom relief reported Potential fertility preservation via metabolic profile improvement Mehdizadehkashi et al. 28 Metabolic regulation Atorvastatin, resveratrol Rat endometriosis model, human endometriotic stromal cells Inhibit glycolysis, reduce angiogenesis via GLUT/MCT modulation May reduce inflammatory pain indirectly Potential to slow lesion growth, improve fertility environment Bahrami et al. 48 Plantago ovata Patient-derived endometriotic stromal cells ( in vitro ) Alters LDHA, PDH, and PDK1/3 activity; induces apoptosis Not reported Potential to improve implantation environment by reducing ectopic cells Cho et al. 110 OXPHOS inhibitors Curcumin, plumbagin, atovaquone Mouse endometriosis model Inhibit OXPHOS, increase ROS, induce cell death Analgesic properties reported with curcumin in models Not reported Kapur et al. 57 Bioactive substances DMF Human endometriotic stromal cells ( in vitro ) Lowers ΔΨm, disrupts Ca 2+ , induces ROS Not reported Potential fertility benefit Cho et al. 110 NADA Human endometriotic stromal cells ( in vitro ) CB1 activation, ROS generation, mitochondrial failure in stromal cells Not reported Not reported Gamisonia et al. 111 6,8-Dicoumaroside Human endometriotic stromal cells ( in vitro ) Alters ΔΨm, reduces ATP Not reported Not reported Song et al. 112 Other mitochondria-modulating agents Fraxetin Human endometriotic stromal cells ( in vitro ) Disrupts ΔΨm, OXPHOS, induces apoptosis Not reported Potential to reduce recurrence, improve reproductive outcome Ham et al. 113 Baicalein Human ovarian endometriosis mesenchymal stromal cells ( in vitro ) Increases mitochondrial depolarization, ROS via Ca 2+ influx Not reported Potential fertility benefit by reducing lesion load Ham et al. 113 ALDH2 activator (Alda-1) Mouse endometriosis model (pain behavior assessment) Reduces 4-HNE-mediated sensitization of TRPV1/ASIC3 Reduces endometriosis-associated pain behaviors in mouse models Not reported Cacciottola et al. 67 Iron overload and ferroptosis regulation (HMOX1 protective role) Mouse endometriosis model, human ovarian granulosa cells Modulates iron overload-induced oxidative stress Alleviates inflammation and pain via oxidative stress reduction Protects mitochondrial function in granulosa cells and early embryos, improving developmental potential Tang et al. 60 PHB1 regulation Human ovarian granulosa cells (patient derived) Modulates glucose metabolism in granulosa cells Not reported Potential to improve oocyte quality by correcting metabolic dysfunction Gołąbek-Grenda et al. 100 mtDNA copy number/mutation intervention Human plasma and oocyte samples (clinical) Restores mitochondrial energy supply Not reported Potential to improve fertilization rate and embryo development via autophagy enhancement or NAD+ supplementation Creed et al., 106 Li et al. 107 Mitochondria-targeted therapies and their effects on pain and infertility in endometriosis Treatment selection for patients with endometriosis must consider the patient’s age at diagnosis, disease stage, symptoms, expectations, conception plans, safety, incidence of adverse effects, tolerability, and cost. The medical therapy of endometriosis must be regarded as part of a comprehensive long-term therapeutic approach aimed at controlling pain symptoms, preserving fertility capability, and preventing postoperative recurrence. Currently available pharmacologic treatments for endometriosis predominantly depend on hormonal medications (e.g., combination oral contraceptives, progestins, danazol, and gonadotropin-releasing hormone analogs), which inhibit ovarian function but do not provide a cure for the condition. Consequently, individuals with endometriosis require an immediate long-term non-hormonal treatment that preserves fertility. 114 Mitochondria-centric therapeutic approaches present novel opportunities for prospective treatment. Modulating mitochondrial activity to restore normal cellular metabolism and energy balance may effectively alleviate endometriosis symptoms and enhance reproductive results in patients. Considering the significant involvement of mitochondria in endometriosis, researchers have suggested various therapeutic techniques focused on modulating mitochondrial function to restore normal mitochondrial activity and energy metabolism, while also limiting the development and progression of endometriosis. Antioxidants mitigate OS by diminishing the buildup of ROS in mitochondria, thereby alleviating the symptoms of endometriosis. Natural plant-derived small-molecule compounds, including methyl 3,4-dihydroxybenzoic acid (MDHB), enhance mitochondrial function, restore ΔΨm and ATP synthesis, mitigate OS, and further inhibit OS conditions by upregulating the expression of the antioxidant transcription factor Nrf2 and antioxidant enzymes such as SOD1, NQO1, and glutamate-cysteine ligase catalytic subunit (GCLC), thereby improving oocyte and embryo quality. 107 , 108 In a murine model of endometriosis, vanillin demonstrates antioxidant properties, markedly diminishes ROS intensity in localized tissues, and suppresses the production of mitochondrial complex IV. 109 Naringenin regulates the redox state by lowering mitochondrial potential, inducing apoptosis, and inhibiting cell proliferation. It accomplishes this by enhancing the expression of Nrf2 and its downstream effectors (e.g., NQO1 and HO-1) while diminishing the expression of KEAP1, an inhibitory molecule. 68 In addition to findings from in vitro and animal studies, several randomized controlled clinical trials have explored the role of antioxidant supplementation in endometriosis management. Nodler et al. reported that supplementation with vitamin D or ω-3 fatty acids significantly improved the inflammatory profiles in adolescent girls and young women with endometriosis, suggesting potential benefits for symptom relief and disease modulation. 26 Amini et al. demonstrated that combined supplementation with vitamin C and vitamin E reduced OS markers and alleviated pain in women with endometriosis. 27 Similarly, Mehdizadehkashi et al. found that vitamin D supplementation improved clinical symptoms and metabolic profiles in affected patients. 28 These results indicate that antioxidant-based interventions may exert therapeutic effects not only in experimental models but also in clinical practice, offering a promising non-hormonal option for symptom management and potential fertility preservation in endometriosis. Metabolic abnormalities in cells associated with endometriosis, particularly changes in glycolysis and fatty acid oxidation, are significant contributors to disease progression. Research indicates that focusing on the modulation of fatty acid oxidation and glycolysis pathways could represent a novel treatment approach. Pharmaceuticals like statins (atorvastatin) and resveratrol attenuate glycolysis and impede neoangiogenesis by modulating the expression of glucose transporter proteins (GLUT-1 and GLUT-3) and monocarboxylic acid transporter proteins (MCT-1 and MCT-4), potentially decelerating the advancement of endometriosis. 48 Plantago ovata markedly induced apoptosis in the endometrial cells of individuals with endometriosis by altering the activity or expression of aerobic glycolytic enzymes (e.g., LDHA, pyruvate dehydrogenase, and pyruvate dehydrogenase kinase 1/3), 110 demonstrating the potential to influence mitochondrial function via metabolic pathways. Inhibition of OXPHOS may offer novel therapeutic strategies for treating endometriosis. OXPHOS inhibitors, including curcumin, plumbagin, and atovaquone, have been validated in mouse endometriosis models, where they suppress mitochondrial complex activity, elevate intracellular ROS levels, and trigger apoptotic cell death, thereby reducing lesion growth. Curcumin additionally exhibits analgesic effects in animal models, potentially via ROS-mediated anti-inflammatory pathways. These agents disrupt mitochondrial ATP production, impair the bioenergetic capacity of ectopic endometrial cells, and promote cell clearance. 57 Numerous bioactive substances exert considerable influence on mitochondrial function and cellular metabolism, also indicating potential for endometriosis treatment. Fraxetin inhibits cellular proliferation and migration by modulating the P38/JNK/ERK pathway and the AKT/S6 pathway. It disrupts ΔΨm, interferes with OXPHOS, and induces endoplasmic reticulum stress and endogenous apoptosis, thereby decelerating baicalein in human ovarian endometriosis mesenchymal stromal cells and increasing mitochondrial depolarization and ROS production via calcium influx, leading to cell death and potential reduction in lesion burden. 113 5,7-Dimethoxyflavone (DMF) decreases ΔΨm, disrupts intracellular calcium homeostasis, and promotes ROS formation, ultimately triggering apoptosis in human endometriotic stromal cells. 110 N-amidodopamine (NADA) exhibits significant selectivity in inducing death in endosomal ectopic stromal cells through the activation of CB1 receptors, and subsequently engaging serine palmitoyl transferase and nitric oxide synthase, thereby facilitating ROS formation and mitochondrial failure. 111 Moreover, 6,8-dicoumaroside alters ΔΨm and reduces ATP production in endometriotic stromal cells. This suppresses cell proliferation, indicating possible therapeutic utility. 112 Beyond their antioxidant and anti-proliferative effects, these observations also suggest that altered calcium homeostasis may represent an additional dimension of mitochondrial dysfunction in endometriosis, given its close links to ΔΨm, ROS generation, ATP production, and apoptosis. However, compared with OS and metabolic reprogramming, the role of mitochondrial calcium homeostasis in endometriosis remains insufficiently characterized.

All authors read and approved the final version of the manuscript. Y.S.R. proposed the idea and drafted the manuscript. J.Zhu contributed to data collection. C.C.W., J.Zhang, and Y.C.C. critically revised the manuscript for important intellectual content.

Aberrant mitochondrial function in endometriosis disrupts cellular energy production, shifting metabolism from OXPHOS to glycolysis, like the Warburg effect. This metabolic reprogramming not only enhances the endometriotic cell survival under hypoxia but also promotes OS, which exacerbates tissue damage. These key mechanisms are summarized in Table 1 , highlighting the role of mitochondrial dysfunction in endometriosis. Table 1 Aberrant mitochondrial function associated with endometriosis Functions Description and summary Related genes/proteins Potential mechanisms Validation model (cell type/human/animal/organ) Correlate with clinical phenotype Potential therapeutic implications (preclinical/conceptual) Reference Metabolic reprogramming in endometriosis Regulates energy metabolism, affecting glucose and lactate levels, contributing to infertility. PHB1 Granulosa cell metabolic dysregulation → impaired oocyte quality Human granulosa cells from endometriosis patients; in vitro assays Infertility/reduced oocyte quality Potential target to restore granulosa cell mitochondrial metabolism; requires further validation Mao et al. 16 Energy imbalance and metabolic reprogramming toward glycolysis. HIF1A , HK2 , PKM2 , PDK1 , G6PD , LDHA Reduced OXPHOS, increased glycolysis (Warburg-like shift) Human ectopic/eutopic lesions; nonhuman primate model; in vitro ESCs Glycolytic shift correlates with disease stage/severity Target glycolysis (DCA/PDK1, LDHA inhibitors); OXPHOS inhibitors; metabolic modulators (resveratrol, atorvastatin) Li et al., 23 Ghosh et al., 42 Hoffmann-Młodzianowska et al., 43 Wu et al., 44 Sreerangaraja Urs et al., 45 Atkins et al. 46 OXPHOS pathway inhabitation, metabolic reprogramming in response to hypoxia. HIF1A , HK2 , PKM2 , PDK1 , G6PD , LDHA HIF1A-driven glycolysis; TGF-β1 upregulates HIF1A, LDHA, PDK1, and SLC2A1 in adjacent mesothelial cells Human lesions; peritoneal mesothelial cells; in vitro ESCs Associated with lesion survival and stage progression HSF1 inhibitor KRIBB11; DCA (PDK targeting); LDHA inhibition Sreerangaraja Urs et al., 45 Kobayashi et al., 47 Bahrami et al., 48 Ren et al., 49 Khashchenko et al. 50 Increased glycolysis despite mitochondrial dysfunction. HIF1A , HK2 , PKM2 , PDK1 , G6PD , LDHA Suppressed OXPHOS with increased lactate production Human ectopic tissues; fibroblasts from pelvic peritoneal lesions Supports ectopic cell survival and invasion Glycolysis inhibitors (e.g., PDK1/LDHA); metabolic modulators Kobayashi et al., 47 Bahrami et al., 48 Hou et al., 51 Wang et al., 52 Horne et al., 53 Lu et al., 54 Zheng et al. 55 Upregulation of glycolysis-related genes. HIF1A , HK2 , PKM2 , PDK1 , G6PD , LDHA Shift toward glycolysis Human ectopic/eutopic tissues; in vitro Correlates with lesion burden and activity PDK1/LDHA inhibitors; GLUT modulation; AURKA inhibition Hou et al., 51 Wang et al., 52 Horne et al., 53 Lu et al., 54 Zheng et al. 55 Inhibition of mitochondrial respiration. PDK1 , LDHA PDK1 inhibits PDH; LDHA maintains glycolytic flux Human endometriosis tissues and cell lines Linked to apoptosis resistance and migration Dichloroacetate (PDK inhibitor); LDHA inhibition Kim et al. 56 Shift to glycolysis due to impaired mitochondrial biogenesis. HIF1A , HK2 , PKM2 , PDK1 , G6PD , LDHA Reduced mitochondrial content/function → glycolytic compensation ESCs; human lesions (observational) Supports survival in hypoxia OXPHOS inhibitors (curcumin, plumbagin, atovaquone) Kapur et al. 57 Enhancement of mitochondrial function, suppression of glycolysis. HIF1A , HK2 , PKM2 , PDK1 , G6PD , LDHA Heme-driven OXPHOS activation; progesterone-resistant profiling In vitro and mouse models Promotes lesion progression Avoid heme exposure; potential targeting of heme/HO-1 axis (investigational) Ma et al. 58 Transition between glycolysis and OXPHOS. HIF1A , HK2 , PKM2 , PDK1 , G6PD , LDHA Metabolic plasticity depending on microenvironment Human lesions; lesion location-specific respiration differences Heterogeneous metabolic profiles across lesion sites Combination metabolic targeting (glycolysis + OXPHOS)—concept stage Kobayashi et al., 47 Bahrami et al., 48 Ma et al. 58 Upregulation of ETC/OXPHOS genes in IL-17RE + Th17 cells. NDUFB5 , MT-CO1 , UQCRC1 , NDUFS6 Increased ROS production fuels inflammatory response Human peritoneal fluid (single-cell RNA-seq) Identified in moderate/severe disease; inflammatory phenotype Concept: OXPHOS modulation in pathogenic Th17 cells Jiang et al. 59 Mitochondrial morphological changes due to oxidative stress. HIF1A , HK2 , PKM2 , PDK1 , G6PD , LDHA Elongation/cristae changes → higher ROS and glycolysis ESC morphology studies Enhanced survival and migration Nrf2/AMPK activation; antioxidants Assaf et al., 4 Chen et al. 5 RNF43/NDUFS1 axis modulates complex I and ROS. RNF43, NDUFS1 Increased OXPHOS → ROS → pro-survival/migration Human ectopic tissues; in vitro Associated with lesion aggressiveness (experimental) Concept: restore RNF43 or target complex I activity Tang et al. 60 Oxidative stress i endometriosis Increased ROS production and reduced antioxidant activity. NRF2 , KEAP1 , NQO1 , HMOX1 ROS-mediated DNA/protein/lipid damage Patient samples and observational studies Infertility Antioxidants (e.g., vitamins C & E) Hung et al., 21 Kaltsas et al. 61 Increased oxidative stress, altered ROS production. NRF2 , KEAP1 , NQO1 , HMOX1 Upregulated pro-oxidant enzymes; reduced protective factors Ectopic lesion analyses Lesion establishment and persistence Antioxidants (resveratrol, vanillin) Cacciottola et al., 62 Kaltsas et al., 61 Imanaka et al., 63 Thézénas et al. 64 Iron overload, ROS production, mitochondrial damage. NRF2 , KEAP1 , NQO1 , HMOX1 Cytochrome c release; ferroptosis initiation Granulosa cells and mouse embryo models Embryotoxicity; infertility Preserve mitochondrial function; HMOX1 pathway; potential iron chelation Wu et al., 65 Chen et al. 66 Mitochondrial damage due to ROS, enhanced cell migration. NRF2 , KEAP1 , NQO1 , HMOX1 ROS activates pro-proliferative signaling (e.g., Raf/MEK/ERK) ESC metabolic assays (OCR/ECAR) Lesion progression Antioxidants; NF-κB pathway modulation Assaf et al., 4 Chen et al., 5 Cacciottola et al. 62 Iron-induced ROS, ferroptosis, impaired development. NRF2 , KEAP1 , NQO1 , HMOX1 Mitochondrial dysfunction, membrane hyperpolarization Mouse models (pre-implantation embryos) Reduced embryo development; infertility HMOX1-mediated protection; ferroptosis modulation (investigational) Chen et al. 66 Facilitates pathological alterations including migration and implantation. RAF, MEK, ERK ROS → MAPK activation In vitro signaling studies in ESCs Lesion invasiveness Antioxidants; pathway-specific inhibitors (investigational) Assaf et al., 4 Cacciottola et al. 67 Activation of Nrf2 modulates antioxidant response. NRF2 , KEAP1 Nrf2-driven antioxidant enzymes (NQO1, HO-1) Rat endometriosis model; in vitro Reduced lesion growth in models Nrf2 activators (e.g., naringenin) Kapoor et al. 68 Damage to oocyte quality due to oxidative stress and mitochondrial dysfunction. NRF2 , KEAP1 , NQO1 , HMOX1 Reduced ATP, increased ROS; altered antioxidant gene expression Human oocyte/granulosa cell studies; scRNA-seq Infertility; poorer oocyte competence Antioxidants; MDHB to activate Nrf2 in granulosa cells Cacciottola et al., 62 Wang et al., 69 Ferrero et al. 70 Compromised ART success due to mitochondrial dysfunction. NRF2 , KEAP1 , NQO1 , HMOX1 Exosome-induced mitochondrial impairment; PHB1-related granulosa cell defects; ART procedure stress Embryo development assays; clinical observational studies Lower implantation/pregnancy rates Antioxidant optimization before/during ART (concept); improve mitochondrial health Mao et al., 16 Shi et al., 71 Li et al., 72 Ducreux et al. 73 General link between oxidative stress, mitochondrial dysfunction, and infertility. NRF2 , KEAP1 , NQO1 , HMOX1 Multiple ROS-driven injuries to gametes and endometrium Clinical and experimental evidence Infertility Lifestyle + antioxidants (concept) Garcia-Fernandez and García-Velasco, 74 Ducreux et al. 73 4-HNE-protein adduct formation; nociceptor sensitization via TRPV1/ASIC3 activation. ALDH2 , TRPV1 , ASIC3 Lipid peroxidation products activate nociceptors; impaired aldehyde detoxification Human peritoneal fluid; mouse pain/lesion models Pain severity correlates with oxidative biomarkers ALDH2 activator (Alda-1) reduces lesions and pain in mice McAllister et al., 39 Trevisani et al., 75 Polak et al. 76 NF-κB-mediated cytokine release; MMP-dependent ECM remodeling; Th1/Th2 polarization. IL-1Β , TNF-Α , NF-ΚB , MMPS Sustained inflammatory signaling and neuroangiogenesis Patient microenvironment analyses; mouse models Pelvic pain and hyperalgesia NF-κB inhibition (e.g., nobiletin); antioxidants (resveratrol/stilbenes) Cirillo et al., 77 Cuffaro et al., 78 Nanda et al., 79 Wei et al. 80 mtDNA abnormalities in endometriosis Mitochondrial mutations and polymorphisms linked to endometriosis risk T16172C, C16290T ; A13603G ; M5 haplotype ; AC523-524 del Potential impact on mitochondrial function and susceptibility Human genetic association studies Disease risk (population-dependent) No direct therapy; potential risk stratification Li et al., 15 Govatati et al. 81 Compromised mitochondrial activity, aberrant oocyte growth, and inadequate energy production. Unknown Altered mtDNA copy number reflects mitochondrial dysfunction Follicular fluid/plasma and oocyte studies Infertility; poorer IVF outcomes Biomarker for prognosis; optimize mitochondrial health Chen et al., 5 Peng et al., 41 Huo et al. 82 TFAM +35G/C polymorphism correlates with increased endometriosis risk. TFAM, +35G, C mtDNA transcription/replication factor variation Human genetic study Disease susceptibility No direct therapy; potential genetic marker El Derbaly et al. 14 Impact respiratory chain genes (complex I, ATP synthase, tRNA). mtDNA genes , ( (1.2-, 3.7-, 8.7-kb deletions ) ETC compromise → OXPHOS defects Plasma biomarker studies Diagnostic utility in symptomatic women No direct therapy; noninvasive diagnostic marker Creed et al., 83 Harbottle et al. 84 mtERβ regulates mtDNA gene expression and modulates cell migration in lesions. MTERΒ Anti-apoptotic signaling via Mn-SOD, Bcl2 Human endometriosis cells ( in vitro ) Lesion progression Concept: ERβ modulation; requires validation Liao et al. 11 Affects cell function, leading to mitochondrial energy production imbalance. Unknown Structural dysfunction → reduced ATP, increased ROS ESC ultrastructure studies Potential link to lesion viability Target mitochondrial dynamics/quality control (concept) Chen et al. 5 ETC, electron transport chain; IVF, in vitro fertilization; scRNA-seq, single-cell RNA sequencing. Aberrant mitochondrial function associated with endometriosis ETC, electron transport chain; IVF, in vitro fertilization; scRNA-seq, single-cell RNA sequencing. Recent studies indicate a substantial correlation between the development of endometriosis and mitochondrial malfunction, especially an imbalance in energy metabolism. Mitochondria are essential organelles for cellular energy productions and metabolic control, typically fulfilling cellular energy demands by synthesizing ATP via OXPHOS when adequate oxygen is available. 42 Endometriotic cells experience hypoxic stress during the development of ectopic foci. 23 , 43 Under hypoxic conditions, the cells experience epigenetic regulation and activate many survival mechanisms, including metabolic changes. 44 This is associated with compromised mitochondrial function, as demonstrated by diminished membrane potential and notable reduction in OXPHOS, resulting in decreased ATP generation and insufficient energy supply. 45 Analysis of mitochondrial respiration measures indicated that the oxygen consumption rate (OCR) and respiratory control rate of ectopic endometrial tissue were markedly inferior to those of normal endometrium. 46 Targeted metabolomics revealed a considerable reduction of many mitochondrial metabolites (e.g., creatine, NADH, FAD, tryptophan, and malate) in ectopic tissues. The reduction in mitochondrial energy production may also result from OS-related damage to mtDNA or membranes, alterations in cellular metabolism, or a decrease in energy substrates. 46 This dysfunction of mitochondrial activity not only disrupts normal cellular metabolic activities but also may restrict the cell’s capacity for survival and proliferation. However, in reaction to this deficiency in energy production, endometriotic cells experience metabolic reprogramming, characterized by increased glucose uptake, lactate formation, and aerobic glycolysis. 47 , 48 The mitochondrial OXPHOS pathway is inhibited, while the glycolysis pathway is markedly enhanced, resulting in a metabolic shift akin to the Warburg effect, where energy production is sustained by elevating glycolysis rates despite inadequate mitochondrial energy supply. This metabolic alteration is intricately linked to the clinical stages of endometriosis. 45 , 49 , 50 In comparison to normal endometrium, ectopic endometrium exhibits significantly elevated expression levels of glycolysis-related molecules, including hypoxia-inducible factor 1α (HIF1A), hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), pyruvate dehydrogenase kinase 1 (PDK1), glucose-6-phosphate dehydrogenase (G6PD), and lactate dehydrogenase A (LDHA). 51 , 52 , 53 , 54 , 55 Fibroblasts in pelvic peritoneal ectopic lesions also exhibited markedly elevated glucose utilization and lactate synthesis. 53 The Warburg effect in endometriosis underlies its pathophysiology and is modulated by molecular regulators and drug-targetable pathways. Endometriotic cells can augment glucose uptake and facilitate glycolysis by elevating the expression of glucose transporter proteins, including glucose transporters (GLUT). 48 Heat shock factor 1 (HSF1) augments glycolysis by upregulating the expression of the glycolysis-related gene 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), thereby enhancing cellular metabolism, whereas its inhibitor, KRIBB11, markedly impedes the advancement of endometriosis. 24 Transforming growth factor β1 (TGF-β1) can enhance the expression of glycolysis-associated genes, including HIF1A, LDHA, PDK1, and solute carrier family 2 member 1 (SLC2A1, also known as GLUT1), in peritoneal mesothelial cells adjacent to endometriotic lesions. 53 The expression of LDHA is markedly heightened in endometriosis tissues and is further augmented in hypoxic conditions. The suppression of LDHA led to compromised mitochondrial function, heightened apoptosis, and the inhibition of glycolysis and cell migration, underscoring its significant role in aberrant mitochondrial metabolism in ectopic lesions. PDK1 impedes mitochondrial respiration by inhibiting pyruvate dehydrogenase (PDH), hence obstructing the conversion of pyruvate to acetyl-coenzyme A. Inhibition of PDK1 expression promotes apoptosis in endometriotic cells. 56 Recent findings indicate that the expression of Aurora kinase A (AURKA) is elevated in ovarian endometriosis. AURKA upregulates estrogen receptor β (ERβ); facilitates the proliferation, migration, and invasion of endometriotic cells; and amplifies the metabolic activity of ovarian endometriotic cells via the activation of the glycolytic pathway. In a murine model, the inhibition of AURKA by alisertib halted the advancement of ovarian endometriosis. 85 The elevated expression of prohibitin 1 (PHB1) in the granulosa cells of individuals with endometriosis led to atypical glucose metabolism, as demonstrated by heightened glucose consumption and increased lactate generation. PHB1 may diminish energy loss by modulating mitochondrial function, thereby influencing oocyte quality and cellular metabolism, ultimately resulting in infertility. 16 The observations indicate that mitochondrial biogenesis is compromised in endometriotic cells, which provide energy and promote survival by upregulating genes associated with aerobic glycolysis. Conversely, it has been established that inhibitors of OXPHOS can impede endometrial cell proliferation, 57 while heme can enhance mitochondrial respiration and suppress glycolysis via the mitochondrial OXPHOS pathway, ultimately facilitating the progression of endometriosis damage. 58 Through single-cell RNA sequencing of peritoneal fluid cells from endometriosis patients, Jiang Y et al. demonstrated that mitochondrial OXPHOS drives the pathogenic functions of interleukin-17 receptor E-positive (IL-17RE+) T helper 17 (Th17) cells in peritoneal fluid by enhancing ATP and ROS production, thereby promoting inflammation response in endometriosis. 59 This conflicting outcome may stem from the fact that certain research were conducted on human ectopic endometrial lesions of varying origins or locations, or utilized non-human animals. Consequently, researchers including Konstantin et al. conducted an in vitro analysis of mitochondrial respiration intensity in endometrial biopsy samples from control people and patients with various locations of endometriosis. The study’s results demonstrated that endometriotic lesions showed a reduced rate of oxygen uptake and overexpression of pyruvate kinase M1/2, which may imply a shift toward the glycolytic pathway. 86 Some researchers have suggested that endometriotic cells may temporarily transition their energy metabolism from glycolysis to OXPHOS to preserve mitochondrial function and improve cellular energy production, owing to their chronic dependence on glycolytic processes and inadequate ATP synthesis. 47 Collectively, these findings may suggest that endometriotic cells exhibit metabolic plasticity, dynamically switching between glycolytic and OXPHOS pathways in response to microenvironmental demands. OS refers to an imbalance between ROS and antioxidants, resulting in cellular damage. OS occurs when excess ROS surpass the detoxification or repair capabilities of biological systems. 87 This mechanism is crucial in oocyte senescence and various disorders impacting female reproductive health, particularly in the start and progression of endometriosis and its pathogenesis, where it contributes to lesion establishment through cellular damage, inflammatory activation, and pro-survival signaling in ectopic cells. 4 , 88 , 89 Patients with endometriosis demonstrate elevated ROS production and diminished free radical scavenging ability. 21 Impaired OXPHOS in endometriotic cells results in persistent expression of glycolytic enzymes, which diminishes mitochondrial biosynthesis and causes excessive generation of ROS. 4 Typically, cells necessitate a specific level of ROS to sustain their physiological functionality. At low concentrations, ROS function as signaling molecules in several pathways, including cell proliferation, differentiation, and survival. Conversely, at elevated concentrations, ROS can inflict damage on DNA, lipids, and proteins and trigger cellular autophagy and apoptosis pathways. 62 Excess production of ROS coupled with an inadequate response from the antioxidant defense system adversely impacts the female reproductive system. This effect may result in damage to oocytes and follicles, subsequently impacting fertilization, endocrine function, and endometrial health, ultimately causing infertility. 61 Endometriotic lesions exhibit elevated OS, supported by certain measures of redox substances. Substantially elevated concentrations of iron-related compounds (e.g., total iron, heme iron, free iron, oxyhemoglobin HO, and methemoglobin) and markedly increased levels of antioxidants (e.g., bilirubin, heme oxygenase-1 [HO-1], and total antioxidant capacity) have been observed in the cystic fluids of ectopic cysts compared to non-endometriosis patients. Additional research has identified increased levels of OS indicators in patients. 61 , 63 Marie et al. identified the up-regulation of pro-oxidant enzymes and the down-regulation of protective factors (e.g., enol reductase PTGR1 and methionine sulfoxide reductase) in ectopic foci of endometriosis, which were significantly correlated with a condition of elevated OS. 64 The atypical OS condition in endometriosis patients is evidenced not only by modifications in iron-related chemicals and antioxidants but also by changes in mitochondrial shape. Marked morphological and structural disparities were noted in the mitochondria of endometrial stromal cells (ESCs) from endometriosis patients relative to those from healthy women. Compared with controls and eutopic ESCs, ectopic ESCs showed more and elongated mitochondria. Over 60% were class I (dense matrix, abundant cristae; high ATP capacity), with fewer class II (disorganized, circular cristae; stress-related changes) and rare class III (severe cristae loss; functional impairment). These morphological shifts reflect enhanced metabolic activity, a glycolytic shift, and increased ROS generation in ectopic ESCs. 4 , 5 The intricate interplay between OS and mitochondrial dysfunction in endometriosis significantly affects pathogenic alterations, cellular proliferation, and migration. Mitochondria serve as a primary source of intracellular ROS, which are by-products of the electron transport chain and OXPHOS processes involved in cellular ATP synthesis. 90 Normal mitochondria preserve cellular redox equilibrium by eliminating ROS, whereas dysfunctional mitochondria result in ROS buildup, thus inducing intracellular OS. ROS encompass superoxide anion (O 2 −− ), hydroxyl radicals (–OH), and hydrogen peroxide (H 2 O 2 ), which inflict damage on the peritoneal epithelium and facilitate the implantation of ectopic endometrial. 5 An increasing body of research indicates a significant correlation between mitochondrial impairment and redox homeostasis in endometriosis. The imbalance between superoxide dismutase (SOD) and catalase activities in endometriotic lesions disrupts the metabolic pathway of ROS, leading to the accumulation of hydrogen peroxide, which intensifies OS and may be a significant mechanism underlying the deterioration of the lesion microenvironment and development. As a signaling molecule, ROS can enhance cell proliferation by activating growth signaling pathways associated with cell proliferation, such as the Raf/MEK/ERK pathway. ESCs demonstrate elevated OCR and extracellular acidification rate, hence intensifying the strain on the mitochondrial respiratory chain and augmenting ROS production. 4 Increased ROS levels were identified as contributors to the activation of the Raf/MEK/ERK pathway in ectopic endometrial cells, hence facilitating pathological alterations including cell migration, implantation, and proliferation. 67 AMPK not only regulates OS but also protects against oxidative damage by activating mitochondrial biogenesis, hence preserving redox homeostasis and health. In the endometriosis microenvironment, the downregulation of AMPK may elevate OS, hence intensifying the inflammatory response of the condition. 4 Ring finger protein 43 (RNF43) is downregulated in ectopic endometrial tissues, impacting OXPHOS primarily via modulating the ubiquitination and degradation of NADH ubiquinone oxidoreductase core subunit S1 (NDUFS1), a crucial component of mitochondrial respiratory chain complex I. The downregulation of RNF43 augments mitochondrial OXPHOS, facilitating ROS production and enhancing cell survival and migration. 60 In response to OS, ectopic cells possess a repertoire of defense mechanisms to maintain redox hemostasis prevent apoptosis. ERβ in mitochondria (mtERβ) can augment cellular resistance to oxidative damage-induced apoptosis by promoting the expression of the ROS-scavenging enzyme manganese SOD (Mn-SOD) and the anti-apoptotic protein B-cell lymphoma 2 (Bcl2), indicating a function for mtERβ in reinstating mitochondrial bioenergetics and suppressing mitochondria-dependent apoptosis. 11 Furthermore, integrated proteomics and transcriptomics research has demonstrated that ROS can activate nuclear factor erythroid 2-related factor 2 (Nrf2) to modulate antioxidant responses and mitochondrial biogenesis, thereby alleviating cellular damage and significantly influencing OS and mitochondrial dysfunction. In individuals with endometriosis, the overexpression of the Nrf2/kelch-like ECH-associated protein 1 (KEAP1) pathway intensifies the accumulation of ROS resulting from mitochondrial malfunction; yet, the surplus ROS subsequently activates Nrf2, which further suppresses apoptosis in ectopic lesions. 68 Mitophagy may also participate in mitochondrial dysfunction in endometriosis through dysregulation of mitochondrial quality control. 91 Dysregulated mitophagy could favor the persistence of damaged mitochondria, excessive ROS accumulation, and altered apoptosis, whereas adaptive mitophagy may support mitochondrial turnover and stress tolerance in ectopic cells. In line with this, available evidence implicates both PHB2/PRKN (Parkin)-related mitophagy 92 and PINK1/Parkin-associated pathways in the regulation of mitochondrial homeostasis, apoptosis, and ectopic cells behavior in endometriosis, 93 suggesting that mitophagy may represent an additional mechanism functionally relevant to lesion biology. The association between endometriosis, steroid hormone synthesis capability, and mitochondrial dysfunction is at an initial phase of investigation, and a systematic and thorough body of evidence has yet to be established. Steroid hormones, including estrogen and progesterone, are essential for sustaining reproductive function and modulating the intrauterine environment, with their production being significantly reliant on mitochondrial activity. Mitochondria are crucial in the initial phase of steroid hormone synthesis, facilitating the transport of cholesterol to the outer mitochondrial membrane, where it is transformed to pregnenolone by the cytochrome P450 side chain cleavage enzyme (CYP11A1). 94 The mitochondrial membrane potential (ΔΨm), the mitochondrial proton gradient, and essential enzymes including the steroidogenic acute regulatory (StAR) protein regulate this process. 95 , 96 Research indicates that mitochondrial malfunction in individuals with endometriosis may adversely impact follicular growth, oocyte maturation, and embryo quality, particularly in granulosa cells, by diminishing steroid hormone synthesis. 45 This may be a crucial factor in diminished fertility in individuals with endometriosis. Nonetheless, there is an absence of extensive, systematic research to confirm the correlation between compromised mitochondrial function and reduced steroid hormone synthesis.

A major limitation of the current literature is that biologically heterogeneous specimens are often discussed together as though they represent a single pathogenic process. In reality, OEM, peritoneal endometriosis, and deep infiltrating endometriosis (DIE) develop in distinct anatomical and biochemical environments, with differing exposure to cyclic bleeding, iron deposition, fibrosis, hypoxia, and immune infiltration. These differences are likely to shape mitochondrial function at multiple levels, including redox balance, substrate utilization, dependence on OXPHOS, and stress-response signaling. Thus, current evidence is better interpreted as suggesting, rather than establishing, subtype-specific mitochondrial phenotypes. To date, the evidence is strongest for OEM and peritoneal disease: ovarian lesions are more closely linked to iron-rich cyst fluid, OS, and ovarian dysfunction, 1 , 4 , 5 , 25 , 52 , 62 , 70 , 71 , 82 whereas peritoneal lesions more often reflect local inflammation, mesothelial interactions, glycolytic reprogramming, and OS within the peritoneal milieu. 45 , 49 , 50 , 64 By contrast, direct mitochondrial evidence in DIE remains limited and head-to-head comparisons across lesion subtypes are still lacking. 86 Disease stage further complicates interpretation. Although more advanced disease has been associated with increased OS burden, mtDNA abnormalities, iron overload, or inflammatory activation, 59 , 81 current evidence does not support a consistent linear relationship between stage and any single mitochondrial variable, including OXPHOS status, ROS burden, pain severity, or reproductive impairment. Stage should, therefore, be regarded as a partial clinical descriptor rather than a direct surrogate for mitochondrial dysfunction. A similar need for caution applies to the interpretation of OXPHOS. Several studies have emphasized impaired mitochondrial respiration and enhanced glycolysis in ectopic lesions, consistent with a stress-adaptive shift in energy metabolism. By contrast, studies of peritoneal immune cells suggest that OXPHOS may also sustain pathogenic inflammatory activity, and in some experimental systems, pharmacological inhibition of OXPHOS has shown anti-proliferative or anti-inflammatory effects. 45 , 49 , 50 , 53 , 59 , 64 , 85 , 103 These findings are better understood as reflecting heterogeneity across cell populations, lesion locations, biochemical environments, and model systems than as a true contradiction. Ectopic lesion cells, immune cells, and surrounding stromal or mesothelial components should not be assumed to share the same bioenergetic state. A more coherent framework may, therefore, be to distinguish at least four interrelated but non-equivalent pathogenic layers: lesion-intrinsic ectopic tissue, 1 , 4 , 5 , 25 , 45 , 49 , 50 , 52 , 53 , 60 , 64 , 86 the peritoneal inflammatory and mesothelial niche, 45 , 49 , 50 , 53 , 59 , 64 , 85 , 103 eutopic endometrium as a predisposition layer, 17 , 18 , 19 , 20 , 23 , 43 , 44 , 45 , 46 , 86 and the granulosa cell, oocyte, and embryo layer as a reproductive consequence layer. 12 , 14 , 15 , 16 , 62 , 65 , 66 , 70 , 71 , 72 , 103 , 107 This framework does not exclude crosstalk among compartments, but it helps avoid overstating mechanistic equivalence across tissues and provides a clearer basis for interpreting apparently inconsistent findings. This distinction is particularly important when infertility and therapeutic implications are considered. The strongest mechanistic evidence for reproductive dysfunction concerns OEM, in which OS, iron exposure, and altered bioenergetics in granulosa cells or oocytes may directly impair folliculogenesis, oocyte competence, and embryo developmental potential. 5 , 12 , 14 , 15 , 16 , 62 , 70 , 71 , 82 In non-ovarian lesions, by contrast, the adverse effects of mitochondrial dysfunction on fertility are more likely to be indirect, mediated through inflammation, an altered peritoneal milieu, embryotoxicity, or broader systemic effects rather than direct ovarian injury. 45 , 49 , 50 , 59 , 103 From a therapeutic perspective, mitochondria represent a promising target, but current evidence remains largely preclinical and heterogeneous. Existing studies have mainly focused on antioxidants, metabolic regulators, OXPHOS inhibitors, and several bioactive compounds, whereas more mechanistically defined therapeutic ways, including glycolysis-OXPHOS switching, aldehyde detoxification, disrupted iron handling or ferroptosis, and mitochondrial quality control, have not yet been systematically integrated into a unified therapeutic framework. Accordingly, mitochondria are better regarded at present as a promising therapeutic target than as the basis of an established treatment strategy, and future progress will require lesion subtype-specific, compartment-resolved, and clinically validated approaches. Although this review focuses on endometriosis, emerging evidence also links adenomyosis to mitochondrial dysfunction, including mitochondrial damage, OS, altered mitophagy, and mtDNA-associated inflammatory signaling. 101 , 115 , 116 , 117 However, adenomyosis and endometriosis are distinct clinicopathological entities, and their similarities and differences have already been reviewed elsewhere 118 , 119 ; therefore, detailed discussion of adenomyosis is beyond the scope of the present review.

Mitochondrial dysfunction is increasingly recognized as an important component of endometriosis biology, particularly in relation to metabolic reprogramming, OS, and impaired cellular homeostasis. Current evidence suggests that altered mitochondrial function may contribute to reduced OXPHOS, enhanced glycolytic activity, and increased ROS accumulation in specific lesion types and tissue compartments. However, these alterations are unlikely to be uniform across all forms of endometriosis, and their temporal relationship to disease initiation, progression, pain, and infertility remains incompletely understood. Mitochondrial pathways also represent a promising area for translational investigation. Nonetheless, current therapeutic evidence remains largely preclinical and heterogeneous, and the extent to which mitochondria-targeted strategies can consistently relieve symptoms, improve fertility outcomes, or modify disease progression in patients remains uncertain. Likewise, mtDNA copy number changes and pathogenic variants are of interest as potential biomarkers, but the available evidence is still limited and requires further validation before clinical application. Future research should, therefore, prioritize lesion subtype-specific and compartment-resolved studies, the development of more representative preclinical models, and well-designed translational and clinical investigations. A clearer understanding of when mitochondrial dysfunction is pathogenic, adaptive, or secondary to other disease processes will be essential for translating mechanistic insights into reliable biomarkers and mechanism-based therapeutic strategies for endometriosis.

During the preparation of this work the authors used ChatGPT in order to improve readability and language. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.

Endometriosis is a chronic inflammatory gynecological disorder characterized by the presence of endometrial-like tissue outside the uterus. 1 It affects approximately 10% of women of reproductive age, impacting around 190 million individuals globally. 2 The primary symptoms of endometriosis include pelvic pain, infertility, and discomfort both within and outside the pelvic region. 3 Despite extensive research, the exact pathogenesis remains incompletely understood. Retrograde menstruation is a leading hypothesis for its etiology, but other factors, including hormone imbalances, genetic predispositions, inflammatory responses, pathological angiogenesis, immune system dysregulation, environmental pollutant exposures, and oxidative stress (OS), have also been implicated. 1 , 4 , 5 Conventional treatments, mainly focused on hormone suppression, may have detrimental effects on fertility, while surgical excision of lesions yields varying results across individuals. Given the widespread prevalence and debilitating symptoms, endometriosis imposes a significant burden on both individuals and society, 6 , 7 underscoring the need for improved knowledge of disease mechanisms and management strategies. Mitochondria, the energy powerhouses of the cell, are responsible for producing ATP and biosynthesis via oxidative phosphorylation (OXPHOS) and the tricarboxylic acid (TCA) cycle, processes essential for cellular survival and proliferation. 8 , 9 Beyond their role in energy production, mitochondria regulate cellular functions through mechanisms such as the release of cytochrome c , activation of AMP-activated protein kinase (AMPK), generation of reactive oxygen species (ROS), and the release of mitochondrial DNA (mtDNA) and TCA cycle metabolites. 10 Mitochondria also adjust their function by modulating processes like fusion, fission, selective degradation, and transport. Proper mitochondrial activity is crucial for cellular health, and impairments in mitochondrial function are linked to a variety of disorders, particularly those involving energy-demanding cells, such as muscle, nerve, and reproductive cells. 9 Recent research has increasingly focused on the role of mitochondrial dysfunction in various diseases. In the field of endometriosis, there has been a growing body of research focusing on the role of mitochondrial aberrance, with increasing evidence linking it to the phenotype and pathological progression of the disease. 11 , 12 In endometriosis, ectopic endometrial cells are exposed to prolonged hypoxia and experience significantly elevated energy demands, 13 leading to compromised mitochondrial functions. To meet these energy demands, these cells undergo metabolic reprogramming, shifting from OXPHOS to glycolysis, a process akin to the “Warburg effect” in tumor. 4 This metabolic alteration is accompanied by changes in mitochondrial morphology and function, including alterations in mitochondrial genetic material. 12 , 14 , 15 , 16 Additionally, mitochondrial dysfunction in endometriotic cells results in excessive ROS production, exacerbating OS and further contributing to disease progression. 17 , 18 , 19 , 20 These cells exhibit robust survival under hypoxic stress, with epigenetic modifications that promote increased cell migration, reduced apoptosis, and enhanced growth potential. 21 , 22 , 23 These changes highlight the complex interplay between mitochondrial dysfunction and endometriosis. It suggests that targeting mitochondrial pathways could offer novel therapeutic avenues for the disease. 4 , 24 , 25 Mitochondrial modulators show great potential in the treatment of endometriosis. These agents can effectively address metabolic dysregulation by improving mitochondrial function and energy metabolism. Antioxidants, such as glutathione and vitamin C, help reduce levels of ROS, thereby alleviating OS and promoting cell survival. Additionally, OXPHOS inhibitors lower cellular energy supply, which can suppress the proliferation and migration of ectopic endothelial cells. Furthermore, certain bioactive substances can induce ROS generation, promoting apoptosis in ectopic cells and aiding in the removal of aberrantly growing tissues. The combined use of these therapeutic strategies offers new hope for improving the health outcomes of patients with endometriosis. This review summarizes the latest research on the relationship between mitochondrial dysfunction and endometriosis, highlighting the role of mitochondrial alterations and exploring the potential for mitochondrial-targeted therapies to improve clinical outcomes for patients with endometriosis. 26 , 27 , 28

The authors declare that they have no competing interests.

Endometriosis-associated pain stems from a complex interplay of multiple pathologic mechanisms that extend beyond the presence of ectopic lesions. Chronic inflammation is the primary driver, in which recurrent bleeding and subsequent intraperitoneal iron-mediated OS activate nociceptive pathways via pro-inflammatory cytokines (IL-1β, IL-8, and TNF-α) and prostaglandins (PGE2). 97 , 98 These mediators induce neurogenic inflammation by sensitizing peripheral nerve endings while promoting neuroangiogenesis, an infiltration of new sensory nerve fibers into endometriotic lesions. 99 Importantly, the pain phenotype often involves both peripheral sensitization (at the site of the lesion) and central sensitization. 99 Emerging evidence suggests that mitochondrial dysfunction in endometriosis may be involved in these processes through overproduction of reactive aldehydes, OS-mediated nociceptive receptor activation, and sustained inflammatory signaling, as detailed in subsequent sections ( Figure 1 ). Figure 1 Mitochondrial dysfunction and endometriosis-associated chronic pelvic pain Created in BioRender. Rong, Y. ( https://BioRender.com/6afv598 ) is licensed under CC BY 4.0. Mitochondrial dysfunction and endometriosis-associated chronic pelvic pain Created in BioRender. Rong, Y. ( https://BioRender.com/6afv598 ) is licensed under CC BY 4.0. Lipid peroxidation generates reactive aldehydes (e.g., 4-HNE) that form nociceptive protein adducts in peritoneal fluid. Clinically, this manifests as a correlation between pelvic pain severity and peritoneal OS biomarkers. 39 , 75 , 76 Concurrently, 4-HNE directly sensitize nociceptors through transient receptor potential vanilloid 1 (TRPV1)/acid-sensing ion channel 3 (ASIC3) channels. The mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2), responsible for detoxifying these harmful aldehydes, exhibits reduced activity in peritoneal fluid of stage IV endometriosis patients, impairing aldehyde clearance. This biochemical alteration correlates with increased pain-related behaviors and lesion formation in animal models. Crucially, studies in mice model demonstrate that enhancing ALDH2 activity with the enzymatic activator Alda-1 prevents endometriotic lesion development and alleviates established pain-related behaviors. 39 These findings establish a mechanistic link between mitochondrial aldehyde metabolism and endometriosis-associated pain. Beyond aldehyde metabolism, chronic inflammation is a parallel driver of nociception in endometriosis. In the pelvic microenvironment, sustained increases in IL-1β, IL-8, TNF-α, and PGE2 sensitize peripheral afferents and promote neurogenic inflammation, thereby heightening hyperalgesia. Persistent cytokine signaling can augment mitochondrial ROS generation, intensifying OS and creating a self-reinforcing feedback loop that links inflammation, OS, and pain. 77 , 78 Central to this loop is nuclear factor-kappa B (NF-κB), which amplifies pro-inflammatory cytokines, skews T helper 1 (Th1)/T helper 2 (Th2) responses, and induces extracellular matrix remodeling through matrix metalloproteinase (MMP) changes that facilitate sensory fiber ingrowth and signal amplification. 79 Consistent with this mechanism, inhibiting NF-κB reduces inflammatory mediators and alleviates pain behaviors in experimental settings, supporting its therapeutic relevance. 79 , 80 Notably, natural antioxidants such as resveratrol and its stilbene analogs (e.g., pterostilbene and piceatannol) have shown promise in this context. 100 In addition to its antioxidant and anti-inflammatory properties, resveratrol has also been reported to modulate, and in some settings inhibit, mitochondrial ATP synthase activity, suggesting that its effects may also involve direct regulation of mitochondrial bioenergetics, 101 although direct evidence for this mechanism in endometriosis remains limited. These compounds not only downregulate pro-inflammatory cytokines but also promote ROS detoxification and restore redox homeostasis. By alleviating mitochondrial OS, they may help disrupt the vicious cycle between inflammation and pain, offering novel therapeutic avenues for pain management in endometriosis. Endometriosis may affect a woman’s fertility in a number of ways, including structural abnormalities of the reproductive organs due to pelvic anatomical alterations (e.g., adhesions and tubal dysfunction), diminished ovarian reserve, decreased oocyte quality, and decreased implantation and pregnancy rates due to altered endometrial permissiveness. These factors have been extensively studied and recognized as the main causes of infertility due to endometriosis. 74 Among these factors, OS and impaired mitochondrial function not only have deleterious effects on the ovarian reserve of endometriosis patients but also affect the quality of oocytes and, consequently, the development of the embryo. OS is considered to be an “initiator” of oocyte aging and reproductive pathology, which further deteriorates fertility by causing abnormal follicular degeneration and reduced fertilization rates. 69 Defective mitochondria in oocytes primarily contribute to elevated ROS levels in vivo , with OS being a significant consequence of compromised mitochondrial activity. 102 Oocyte quality is dependent on mitochondrial function and the balance of intracellular ROS levels, which is maintained by the antioxidant enzyme system. Mature oocytes need to provide sufficient substrate to support embryonic development until implantation in the endometrium. Rapid oocyte growth requires an efficient energy source, which is provided by a large number of mitochondria and abundant substrates (e.g., glucose and fatty acids) for the OXPHOS process. However, mature oocytes from patients with endometriosis often exhibit abnormal mitochondrial morphology and decreased mass and altered expression of genes associated with antioxidant responses. These changes may result in limited energy production, which can lead to oocyte arrest and degeneration during fertilization. 62 , 70 Abnormal mitochondria may be associated with relevant components of the focal microenvironment. In the microenvironment of ovarian follicles affected by endometriosis (ovarian endometrioma [OEM]), elevated expression of let-7 miRNAs disrupts mitochondrial ATP energy metabolism in granulosa cells, as well as affects the OS levels of ROS, leading to abnormal function of the granulosa cells, which affects oocyte quality at the molecular level. 71 Tubal exosomes from endometriosis patients increase OS by downregulating the OXPHOS process, decreasing the ΔΨm, and promoting apoptosis, which in turn negatively affects the development of early embryos. 72 In granulosa cells, aberrant expression of PHB1 mitigates energy loss caused by mitochondrial dysfunction by regulating mitochondrial function and altering ROS levels, a mechanism that may partially explain the impaired oocyte quality in patients with endometriosis. 16 Iron overload has been identified as a promoter of ROS, intensifying mitochondrial damage. Iron excess markedly increases the release of mitochondrial cytochrome c , thus triggering death in granulosa cells. 65 In a murine model of endogamy, peritoneal fluid iron excess can induce embryotoxicity and initiate ferroptosis. Pathologically significant concentrations of iron induce apoptosis and ferroptosis by impairing mitochondrial function, thereby influencing pre-implantation embryonic development through mechanisms linked to mitochondrial damage characterized by reduced ATP levels, elevated ROS levels, and hyperpolarization of the ΔΨm. 66 This ferroptotic process can be mitigated by preserving mitochondrial function, with heme oxygenase 1 (HMOX1) playing a crucial role. 103 An increasing number of endometriosis patients are opting for assisted reproductive technologies (ARTs) to address infertility, and recent studies have shown that ART techniques (e.g., in vitro maturation) are associated with mitochondrial dysfunction, including perturbations in OXPHOS and metabolic processes, and that ectopic disease may further reduce the success rate of ART by increasing OS and altering mitochondrial function. 73 Taken together, endometriosis affects oocyte quality and embryo development through OS and mitochondrial dysfunction, which not only affects natural conception but also reduces the success of ART ( Figure 2 ). Therefore, further studies on the molecular mechanisms of endometriosis on reproductive function, especially in terms of OS and mitochondrial function, will help to improve the current treatment strategies and increase the fertility success rate of infertile patients. Figure 2 The connections between mitochondrial dysfunction, metabolic changes, oxidative stress, and infertility in endometriosis Created in BioRender. Rong, Y. ( https://BioRender.com/4cz0u4y ) is licensed under CC BY 4.0. The connections between mitochondrial dysfunction, metabolic changes, oxidative stress, and infertility in endometriosis Created in BioRender. Rong, Y. ( https://BioRender.com/4cz0u4y ) is licensed under CC BY 4.0.

This work was supported by Ningbo Clinical Research Center for Gynecological Diseases (grant no: 2024L002); Ningbo Major Breakthrough Project for High-end Medical and Healthcare Teams (grant no: 2024021020); Zhejiang Province Major Health and Wellness Science and Technology Project Fund (grant no: WKJ-ZJ-2447); Natural Science Foundation of Zhejiang Province (grant no: LY24H040002, LMS25H040004 and LQN26H040009). Natural Science Foundation of Ningbo City (grant no: 2024J375).