Mitochondrial Involvement in the Pathogenesis of Endometriosis and its Potential as Therapeutic Targets

Endometriosis is an estrogen-dependent benign disease characterized by the development of endometrial tissue outside the uterus. This intricate ailment markedly affects a patient’s well-being and lacks a definitive cure. Endometriotic cells enhance their viability by modulating genetic and epigenetic characteristics, with mitochondria being important organelles in determining cellular metabolic pathways. Mitochondrial malfunction is associated with various human disorders, and the disruption of mitochondrial adaptation mechanisms may help develop new therapies for endometriosis. This article examines the significance of mitochondrial balance in the etiology and advancement of endometriosis and introduces several potential drugs targeting mitochondria for its treatment. Similar content being viewed by others

Chapron C, Marcellin L, Borghese B, Santulli P. Rethinking mechanisms, diagnosis and management of endometriosis. Nat Rev Endocrinol. 2019;15:666–82. https://doi.org/10.1038/s41574-019-0245-z. Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet. 2021;397:839–52. https://doi.org/10.1016/S0140-6736(21)00389-5. Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN, Viganò P. Endometriosis. Nat Rev Dis Primers. 2018;4:9. https://doi.org/10.1038/s41572-018-0008-5. Greene R, Stratton P, Cleary SD, Ballweg ML, Sinaii N. Diagnostic experience among 4,334 women reporting surgically diagnosed endometriosis. Fertil Steril. 2009;91:32–9. https://doi.org/10.1016/j.fertnstert.2007.11.020. Bilyk O, Coatham M, Jewer M, Postovit LM. Epithelial-to-Mesenchymal transition in the female reproductive tract: from normal functioning to disease pathology. Front Oncol. 2017;7:145. https://doi.org/10.3389/fonc.2017.00145. Wu MH, Hsiao KY, Tsai SJ, Hypoxia. The force of endometriosis. J Obstet Gynaecol Res. 2019;45:532–41. https://doi.org/10.1111/jog.13900. Kobayashi H, Kimura M, Maruyama S, Nagayasu M, Imanaka S. Revisiting estrogen-dependent signaling pathways in endometriosis: potential targets for non-hormonal therapeutics. Eur J Obstet Gynecol Reprod Biol. 2021;258:103–10. https://doi.org/10.1016/j.ejogrb.2020.12.044. Galluzzi L, Kepp O, Trojel-Hansen C, Kroemer G. Mitochondrial control of cellular life, stress, and death. Circ Res. 2012;111:1198–207. https://doi.org/10.1161/CIRCRESAHA.112.268946. Wischhof L, Scifo E, Ehninger D, Bano D. AIFM1 beyond cell death: an overview of this OXPHOS-inducing factor in mitochondrial diseases. EBioMedicine. 2022;83:104231. https://doi.org/10.1016/j.ebiom.2022.104231. Horne AW, Ahmad SF, Carter R, Simitsidellis I, Greaves E, Hogg C, et al. Repurposing Dichloroacetate for the treatment of women with endometriosis. Proc Natl Acad Sci U S A. 2019;116:25389–91. https://doi.org/10.1073/pnas.1916144116. He X, Liu J, Zang WJ. Mitochondrial homeostasis and redox status in cardiovascular diseases: protective role of the vagal system. Free Radic Biol Med. 2022;178:369–79. https://doi.org/10.1016/j.freeradbiomed.2021.12.255. Tahrir FG, Langford D, Amini S, Mohseni Ahooyi T, Khalili K. Mitochondrial quality control in cardiac cells: mechanisms and role in cardiac cell injury and disease. J Cell Physiol. 2019;234:8122–33. https://doi.org/10.1002/jcp.27597. Adebayo M, Singh S, Singh AP, Dasgupta S. Mitochondrial fusion and fission: the fine-tune balance for cellular homeostasis. FASEB J. 2021;35:e21620. https://doi.org/10.1096/fj.202100067R. Vasquez-Trincado C, Garcia-Carvajal I, Pennanen C, Parra V, Hill JA, Rothermel BA, et al. Mitochondrial dynamics, mitophagy and cardiovascular disease. J Physiol. 2016;594:509–25. https://doi.org/10.1113/JP271301. Pyakurel A, Savoia C, Hess D, Scorrano L. Extracellular regulated kinase phosphorylates Mitofusin 1 to control mitochondrial morphology and apoptosis. Mol Cell. 2015;58:244–54. https://doi.org/10.1016/j.molcel.2015.02.021. Ni HM, Williams JA, Ding WX. Mitochondrial dynamics and mitochondrial quality control. Redox Biol. 2015;4:6–13. https://doi.org/10.1016/j.redox.2014.11.006. Chen H, Vermulst M, Wang YE, Chomyn A, Prolla TA, McCaffery JM, et al. Mitochondrial fusion is required for MtDNA stability in skeletal muscle and tolerance of MtDNA mutations. Cell. 2010;141:280–9. https://doi.org/10.1016/j.cell.2010.02.026. Quintana-Cabrera R, Scorrano L. Determinants and outcomes of mitochondrial dynamics. Mol Cell. 2023;83:857–76. https://doi.org/10.1016/j.molcel.2023.02.012. Friedman JR, Lackner LL, West M, DiBenedetto JR, Nunnari J, Voeltz GK. ER tubules mark sites of mitochondrial division. Science. 2011;334:358–62. https://doi.org/10.1126/science.1207385. Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, et al. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell. 2001;1:515–25. https://doi.org/10.1016/s1534-5807(01)00055-7. Zacharioudakis E, Gavathiotis E. Mitochondrial dynamics proteins as emerging drug targets. Trends Pharmacol Sci. 2023;44:112–27. https://doi.org/10.1016/j.tips.2022.11.004. Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008;27:433–46. https://doi.org/10.1038/sj.emboj.7601963. Otera H, Miyata N, Kuge O, Mihara K. Drp1-dependent mitochondrial fission via MiD49/51 is essential for apoptotic Cristae remodeling. J Cell Biol. 2016;212:531–44. https://doi.org/10.1083/jcb.201508099. Scorrano L, Ashiya M, Buttle K, Weiler S, Oakes SA, Mannella CA, et al. A distinct pathway remodels mitochondrial Cristae and mobilizes cytochrome C during apoptosis. Dev Cell. 2002;2:55–67. https://doi.org/10.1016/s1534-5807(01)00116-2. Ye C, Chen P, Xu B, Jin Y, Pan Y, Wu T, et al. Abnormal expression of fission and fusion genes and the morphology of mitochondria in eutopic and ectopic endometrium. Eur J Med Res. 2023;28:209. https://doi.org/10.1186/s40001-023-01180-w. Lemasters JJ. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res. 2005;8:3–5. https://doi.org/10.1089/rej.2005.8.3. Kung-Chun Chiu D, Pui-Wah Tse A, Law CT, Ming-Jing Xu I, Lee D, Chen M, et al. Hypoxia regulates the mitochondrial activity of hepatocellular carcinoma cells through HIF/HEY1/PINK1 pathway. Cell Death Dis. 2019;10:934. https://doi.org/10.1038/s41419-019-2155-3. Chan NC, Salazar AM, Pham AH, Sweredoski MJ, Kolawa NJ, Graham RL, et al. Broad activation of the ubiquitin-proteasome system by parkin is critical for mitophagy. Hum Mol Genet. 2011;20:1726–37. https://doi.org/10.1093/hmg/ddr048. Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AH, Taanman JW. Mitofusin 1 and Mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet. 2010;19:4861–70. https://doi.org/10.1093/hmg/ddq419. Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. 2010;12:119–31. https://doi.org/10.1038/ncb2012. Twig G, Shirihai OS. The interplay between mitochondrial dynamics and mitophagy. Antioxid Redox Signal. 2011;14:1939–51. https://doi.org/10.1089/ars.2010.3779. Ding WX, Yin XM. Mitophagy: mechanisms, pathophysiological roles, and analysis. Biol Chem. 2012;393:547–64. https://doi.org/10.1515/hsz-2012-0119. Scherz-Shouval R, Elazar Z. Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci. 2011;36:30–8. https://doi.org/10.1016/j.tibs.2010.07.007. Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB, et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol. 2004;6:1221–8. https://doi.org/10.1038/ncb1192. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007;8:741–52. https://doi.org/10.1038/nrm2239. Wanderoy S, Hees JT, Klesse R, Edlich F, Harbauer AB. Kill one or kill the many: interplay between mitophagy and apoptosis. Biol Chem. 2021;402:73–88. https://doi.org/10.1515/hsz-2020-0231. Siracusa R, D’Amico R, Impellizzeri D, Cordaro M, Peritore AF, Gugliandolo E et al. Autophagy and Mitophagy Promotion in a Rat Model of Endometriosis. Int J Mol Sci. 2021; 22. https://doi.org/10.3390/ijms22105074 Zhang L, Liu Y, Xu Y, Wu H, Wei Z, Cao Y. The expression of the autophagy gene beclin-1 mRNA and protein in ectopic and eutopic endometrium of patients with endometriosis. Int J Fertil Steril. 2015;8:429–36. https://doi.org/10.22074/ijfs.2015.4183. Choi J, Jo M, Lee E, Kim HJ, Choi D. Differential induction of autophagy by mTOR is associated with abnormal apoptosis in ovarian endometriotic cysts. Mol Hum Reprod. 2014;20:309–17. https://doi.org/10.1093/molehr/gat091. Yang HL, Mei J, Chang KK, Zhou WJ, Huang LQ, Li MQ. Autophagy in endometriosis. Am J Transl Res. 2017;9:4707–25. Shen HH, Zhang T, Yang HL, Lai ZZ, Zhou WJ, Mei J, et al. Ovarian hormones-autophagy-immunity axis in menstruation and endometriosis. Theranostics. 2021;11:3512–26. https://doi.org/10.7150/thno.55241. Kobayashi H, Imanaka S, Yoshimoto C, Matsubara S, Shigetomi H. Molecular mechanism of autophagy and apoptosis in endometriosis: current Understanding and future research directions. Reprod Med Biol. 2024;23:e12577. https://doi.org/10.1002/rmb2.12577. Liu H, Zhang Z, Xiong W, Zhang L, Xiong Y, Li N, et al. Hypoxia-inducible factor-1alpha promotes endometrial stromal cells migration and invasion by upregulating autophagy in endometriosis. Reproduction. 2017;153:809–20. https://doi.org/10.1530/REP-16-0643. Otera H, Mihara K. Mitochondrial dynamics: functional link with apoptosis. Int J Cell Biol. 2012;2012:821676. https://doi.org/10.1155/2012/821676. Vringer E, Tait SWG. Mitochondria and cell death-associated inflammation. Cell Death Differ. 2023;30:304–12. https://doi.org/10.1038/s41418-022-01094-w. Tait SW, Green DR. Caspase-independent cell death: leaving the set without the final cut. Oncogene. 2008;27:6452–61. https://doi.org/10.1038/onc.2008.311. Shan A, Li M, Li X, Li Y, Yan M, Xian P, et al. BDE-47 decreases progesterone levels in bewo cells by interfering with mitochondrial functions and genes related to cholesterol transport. Chem Res Toxicol. 2019;32:621–8. https://doi.org/10.1021/acs.chemrestox.8b00312. Dmowski WP, Ding J, Shen J, Rana N, Fernandez BB, Braun DP. Apoptosis in endometrial glandular and stromal cells in women with and without endometriosis. Hum Reprod. 2001;16:1802–8. https://doi.org/10.1093/humrep/16.9.1802. Chen C, Zhou Y, Hu C, Wang Y, Yan Z, Li Z, et al. Mitochondria and oxidative stress in ovarian endometriosis. Free Radic Biol Med. 2019;136:22–34. https://doi.org/10.1016/j.freeradbiomed.2019.03.027. Ngo C, Chereau C, Nicco C, Weill B, Chapron C, Batteux F. Reactive oxygen species controls endometriosis progression. Am J Pathol. 2009;175:225–34. https://doi.org/10.2353/ajpath.2009.080804. Zimmet JM, Hare JM. Nitroso-redox interactions in the cardiovascular system. Circulation. 2006;114:1531–44. https://doi.org/10.1161/CIRCULATIONAHA.105.605519. Santulli P, Chouzenoux S, Fiorese M, Marcellin L, Lemarechal H, Millischer AE, et al. Protein oxidative stress markers in peritoneal fluids of women with deep infiltrating endometriosis are increased. Hum Reprod. 2015;30:49–60. https://doi.org/10.1093/humrep/deu290. Assaf L, Eid AA, Nassif J. Role of AMPK/mTOR, mitochondria, and ROS in the pathogenesis of endometriosis. Life Sci. 2022;306:120805. https://doi.org/10.1016/j.lfs.2022.120805. Roberts FL, Markby GR. New insights into molecular mechanisms mediating adaptation to exercise; A review focusing on mitochondrial biogenesis, mitochondrial function, mitophagy and autophagy. Cells. 2021;10. https://doi.org/10.3390/cells10102639. Jendrach M, Mai S, Pohl S, Voth M, Bereiter-Hahn J. Short- and long-term alterations of mitochondrial morphology, dynamics and MtDNA after transient oxidative stress. Mitochondrion. 2008;8:293–304. https://doi.org/10.1016/j.mito.2008.06.001. Lu J, Wang Z, Cao J, Chen Y, Dong Y. A novel and compact review on the role of oxidative stress in female reproduction. Reprod Biol Endocrinol. 2018;16:80. https://doi.org/10.1186/s12958-018-0391-5. Hirschhaeuser F, Sattler UG, Mueller-Klieser W. Lactate: a metabolic key player in cancer. Cancer Res. 2011;71:6921–5. https://doi.org/10.1158/0008-5472.CAN-11-1457. Zhou Y, Jin Y, Wu T, Wang Y, Dong Y, Chen P, et al. New insights on mitochondrial heteroplasmy observed in ovarian diseases. J Adv Res. 2023. https://doi.org/10.1016/j.jare.2023.11.033. Shigetomi H, Higashiura Y, Kajihara H, Kobayashi H. A potential link of oxidative stress and cell cycle regulation for development of endometriosis. Gynecol Endocrinol. 2012;28:897–902. https://doi.org/10.3109/09513590.2012.683071. Bozza MT, Jeney V. Pro-inflammatory actions of Heme and other Hemoglobin-Derived damps. Front Immunol. 2020;11:1323. https://doi.org/10.3389/fimmu.2020.01323. Lousse JC, Van Langendonckt A, Defrere S, Ramos RG, Colette S, Donnez J. Peritoneal endometriosis is an inflammatory disease. Front Biosci (Elite Ed). 2012;4:23–40. https://doi.org/10.2741/e358. Ma XQ, Liu YY, Zhong ZQ, Chen SM, Hu WT, Sheng YR, et al. Heme induced progesterone-resistant profiling and promotion of endometriosis in vitro and in vivo. Biochim Biophys Acta Mol Basis Dis. 2023;1869:166761. https://doi.org/10.1016/j.bbadis.2023.166761. Ito F, Yamada Y, Shigemitsu A, Akinishi M, Kaniwa H, Miyake R, et al. Role of oxidative stress in epigenetic modification in endometriosis. Reprod Sci. 2017;24:1493–502. https://doi.org/10.1177/1933719117704909. Ferreira EM, Giorgi VSI, Rodrigues JK, de Andrade AZ, Jordao AA, Navarro PA. Systemic oxidative stress as a possible mechanism underlying the pathogenesis of mild endometriosis-related infertility. Reprod Biomed Online. 2019;39:785–94. https://doi.org/10.1016/j.rbmo.2019.06.011. Li Y, Zeng X, Lu D, Yin M, Shan M, Gao Y. Erastin induces ferroptosis via ferroportin-mediated iron accumulation in endometriosis. Hum Reprod. 2021;36:951–64. https://doi.org/10.1093/humrep/deaa363. Ansariniya H, Yavari A, Javaheri A, Zare F. Oxidative stress-related effects on various aspects of endometriosis. Am J Reprod Immunol. 2022;88:e13593. https://doi.org/10.1111/aji.13593. Liu M, Wu K, Wu Y. The emerging role of ferroptosis in female reproductive disorders. Biomed Pharmacother. 2023;166:115415. https://doi.org/10.1016/j.biopha.2023.115415. Wan Y, Song Y, Chen J, Kong J, Gu C, Huang J, et al. Upregulated Fibulin-1 increased endometrial stromal cell viability and migration by repressing EFEMP1-Dependent ferroptosis in endometriosis. Biomed Res Int. 2022;2022(4809415). https://doi.org/10.1155/2022/4809415. Wan Y, Gu C, Kong J, Sui J, Zuo L, Song Y, et al. Long noncoding RNA ADAMTS9-AS1 represses ferroptosis of endometrial stromal cells by regulating the miR-6516-5p/GPX4 axis in endometriosis. Sci Rep. 2022;12:2618. https://doi.org/10.1038/s41598-022-04963-z. Li G, Lin Y, Zhang Y, Gu N, Yang B, Shan S, et al. Endometrial stromal cell ferroptosis promotes angiogenesis in endometriosis. Cell Death Discov. 2022;8:29. https://doi.org/10.1038/s41420-022-00821-z. Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB et al. Role of Mitochondria in Ferroptosis. Mol Cell. 2019; 73:354– 63 e3. https://doi.org/10.1016/j.molcel.2018.10.042 Gaschler MM, Hu F, Feng H, Linkermann A, Min W, Stockwell BR. Determination of the subcellular localization and mechanism of action of ferrostatins in suppressing ferroptosis. ACS Chem Biol. 2018;13:1013–20. https://doi.org/10.1021/acschembio.8b00199. Hartwell D, Rodbro P, Jensen SB, Thomsen K, Christiansen C. Vitamin D metabolites–relation to age, menopause and endometriosis. Scand J Clin Lab Invest. 1990;50:115–21. https://doi.org/10.3109/00365519009089142. Delbandi AA, Torab M, Abdollahi E, Khodaverdi S, Rokhgireh S, Moradi Z et al. Vitamin D deficiency as a risk factor for endometriosis in Iranian women. Journal of Reproductive Immunology. 2021; 143. doi: ARTN 103266. 1016/j.jri.2020.103266. Song J, Song G, Park S, Lim W. Inhibitory effects of 6,8-Diprenylorobol on endometriosis progression in humans by disrupting calcium homeostasis and mitochondrial function. Antioxid (Basel). 2022;11. https://doi.org/10.3390/antiox11010171. Song J, Ham J, Park S, Park SJ, Kim HS, Song G, et al. Alpinumisoflavone activates disruption of calcium homeostasis, mitochondria and autophagosome to suppress development of endometriosis. Antioxid (Basel). 2023;12. https://doi.org/10.3390/antiox12071324. Rizzuto R, De Stefani D, Raffaello A, Mammucari C. Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol. 2012;13:566–78. https://doi.org/10.1038/nrm3412. Perrone M, Patergnani S, Di Mambro T, Palumbo L, Wieckowski MR, Giorgi C, et al. Calcium homeostasis in the control of mitophagy. Antioxid Redox Signal. 2023;38:581–98. https://doi.org/10.1089/ars.2022.0122. Walkon LL, Strubbe-Rivera JO, Bazil JN. Calcium overload and mitochondrial metabolism. Biomolecules. 2022;12. https://doi.org/10.3390/biom12121891. Marchi S, Patergnani S, Missiroli S, Morciano G, Rimessi A, Wieckowski MR, et al. Mitochondrial and Endoplasmic reticulum calcium homeostasis and cell death. Cell Calcium. 2018;69:62–72. https://doi.org/10.1016/j.ceca.2017.05.003. Meng F, Li J, Dong K, Bai R, Liu Q, Lu S, et al. Juan-tong-yin potentially impacts endometriosis pathophysiology by enhancing autophagy of endometrial stromal cells via unfolded protein reaction-triggered Endoplasmic reticulum stress. J Ethnopharmacol. 2024;325:117859. https://doi.org/10.1016/j.jep.2024.117859. Al-Hetty H, Jabbar AD, Eremin VF, Jabbar AM, Jalil AT, Al-Dulimi AG, et al. The role of endoplasmic reticulum stress in endometriosis. Cell Stress Chaperones. 2023;28:145–50. https://doi.org/10.1007/s12192-023-01323-2. Choi J, Jo M, Lee E, Lee DY, Choi D. Nuclear factor-kappa B signaling in endometriotic stromal cells is not inhibited by progesterone owing to an aberrant Endoplasmic reticulum stress response: a possible role for an altered inflammatory process in endometriosis. Mol Hum Reprod. 2021;27. https://doi.org/10.1093/molehr/gaab002. Wang QQ, Guo XC, Li L, Gao ZH, Ji M. Treatment with Metformin and Sorafenib alleviates endometrial hyperplasia in polycystic ovary syndrome by promoting apoptosis via synergically regulating autophagy. J Cell Physiol. 2020;235:1339–48. https://doi.org/10.1002/jcp.29051. Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update. 2009;15:441–61. https://doi.org/10.1093/humupd/dmp007. Guo SW, Martin DC. The perioperative period: a critical yet neglected time window for reducing the recurrence risk of endometriosis? Hum Reprod. 2019;34:1858–65. https://doi.org/10.1093/humrep/dez187. Kobayashi H, Matsubara S, Yoshimoto C, Shigetomi H, Imanaka S. The role of mitochondrial dynamics in the pathophysiology of endometriosis. J Obstet Gynaecol Res. 2023;49:2783–91. https://doi.org/10.1111/jog.15791. Ashrafi G, Schwarz TL. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 2013;20:31–42. https://doi.org/10.1038/cdd.2012.81. Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science. 2011;333:1109–12. https://doi.org/10.1126/science.1201940. Dolmans MM, Donnez J. Emerging drug targets for endometriosis. Biomolecules. 2022;12. https://doi.org/10.3390/biom12111654. Li S, Fan Y, Shu C, Zhou Y, Shu J. Methyl 3,4-dihydroxybenzoate alleviates oxidative damage in granulosa cells by activating Nrf2 antioxidant pathway. J Ovarian Res. 2024;17:87. https://doi.org/10.1186/s13048-024-01412-5. Park S, Ham J, Yang C, Park W, Park H, An G, et al. Melatonin inhibits endometriosis development by disrupting mitochondrial function and regulating TiRNAs. J Pineal Res. 2023;74:e12842. https://doi.org/10.1111/jpi.12842. Meresman GF, Götte M, Laschke MW. Plants as source of new therapies for endometriosis: a review of preclinical and clinical studies. Hum Reprod Update. 2021;27:367–92. https://doi.org/10.1093/humupd/dmaa039. Park S, Lim W, Bazer FW, Whang KY, Song G. Quercetin inhibits proliferation of endometriosis regulating Cyclin D1 and its target MicroRNAs in vitro and in vivo. J Nutr Biochem. 2019;63:87–100. https://doi.org/10.1016/j.jnutbio.2018.09.024. Park S, Lim W, Bazer FW, Song G. Naringenin induces mitochondria-mediated apoptosis and Endoplasmic reticulum stress by regulating MAPK and AKT signal transduction pathways in endometriosis cells. Mol Hum Reprod. 2017;23:842–54. https://doi.org/10.1093/molehr/gax057. Ham J, Park W, Song J, Kim HS, Song G, Lim W, et al. Fraxetin reduces endometriotic lesions through activation of ER stress, induction of mitochondria-mediated apoptosis, and generation of ROS. Phytomedicine. 2024;123:155187. https://doi.org/10.1016/j.phymed.2023.155187. Park S, Song G, Lim W. Myricetin inhibits endometriosis growth through Cyclin E1 down-regulation in vitro and in vivo. J Nutr Biochem. 2020;78:108328. https://doi.org/10.1016/j.jnutbio.2019.108328. Park S, Lim W, Bazer FW, Song G. Apigenin induces ROS-dependent apoptosis and ER stress in human endometriosis cells. J Cell Physiol. 2018;233:3055–65. https://doi.org/10.1002/jcp.26054. Ham J, Song J, Song G, Lim W. Autophagy regulation and redox perturbation by Transcrocetin suppress the growth of endometriosis. Biomed Pharmacother. 2024;173:116284. https://doi.org/10.1016/j.biopha.2024.116284. Ham J, Kim J, Bazer FW, Lim W, Song G. Silibinin-induced Endoplasmic reticulum stress and mitochondrial dysfunction suppress growth of endometriotic lesions. J Cell Physiol. 2019;234:4327–41. https://doi.org/10.1002/jcp.27212. Xiang D, Zhao M, Cai X, Wang Y, Zhang L, Yao H, et al. Betulinic acid inhibits endometriosis through suppression of Estrogen receptor Β signaling pathway. Front Endocrinol (Lausanne). 2020;10:604648. https://doi.org/10.3389/fendo.2020.604648. Ryu S, Bazer FW, Lim W, Song G. Chrysin leads to cell death in endometriosis by regulation of Endoplasmic reticulum stress and cytosolic calcium level. J Cell Physiol. 2019;234:2480–90. https://doi.org/10.1002/jcp.26770. Jana S, Paul S, Swarnakar S. Curcumin as anti-endometriotic agent: implication of MMP-3 and intrinsic apoptotic pathway. Biochem Pharmacol. 2012;83:797–804. https://doi.org/10.1016/j.bcp.2011.12.030. Park S, Lim W, Song GA-O. Delphinidin induces antiproliferation and apoptosis of endometrial cells by regulating cytosolic calcium levels and mitochondrial membrane potential depolarization. J Cell Biochem. 2019;120:5072–84. https://doi.org/10.1002/jcb.27784.

We thank Bullet Edits Limited for linguistic editing and proofreading of the manuscript. Funding This study was supported by the National Nature Science Foundation of China (NO. 82305284). Author information Authors and Affiliations Contributions D.Y. Shen wrote the original manuscript and conceived the study; P.W. Hu and J. Li drew pictures and tables; C. Qi revised the final manuscript; Y.H. Shen supervised the study process. Corresponding author Ethics declarations Conflict of Interest The authors declare that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Shen, D., Qi, C., Hu, P. et al. Mitochondrial Involvement in the Pathogenesis of Endometriosis and its Potential as Therapeutic Targets. Reprod. Sci. 32, 935–949 (2025). https://doi.org/10.1007/s43032-025-01827-5 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s43032-025-01827-5