Endometriosis-related infertility focusing on mitochondrial DNA damage and its repair mechanism: Considering treatment strategies

For this narrative review, an extensive search of electronic databases was undertaken to identify relevant studies published up to August 31, 2024.

In oocytes and granulosa cells from endometriosis patients, elevated levels of reactive oxygen species (ROS), driven by hypoxia and oxidative stress, contribute to the accumulation of mtDNA mutations. mtDNA repair is primarily dependent on the base excision repair (BER) pathway, mediated by poly(ADP-ribose) polymerase (PARP-1), due to a deficiency in double-strand break repair mechanisms. Upon mtDNA damage, PARP-1 activates single-strand break repair, utilizing nicotinamide adenine dinucleotide (NAD+) as a substrate. This process depletes ATP and leads to mitochondrial dysfunction in oocytes and granulosa cells. Such mitochondrial impairment may underlie the reduced efficacy of ART in endometriosis patients. Therapeutic interventions aimed at enhancing mitochondrial function, particularly by increasing mitochondrial NAD+ levels, represent a promising approach to addressing endometriosis-associated infertility.

mtDNA mutations and defective repair pathways in endometriosis are key contributors to mitochondrial dysfunction, which compromises ART success. This review highlights the potential of mitochondrial function-enhancing therapies as innovative strategies for improving reproductive outcomes in patients with endometriosis. CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interests for this article. DATA AVAILABILITY STATEMENT No new data were created.

- 1Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN, Vigano P. Endometriosis. Nat Rev Dis Primers. 2018; 4: 9. https://doi.org/10.1038/s41572-018-0008-5 - 2Kok VC, Tsai HJ, Su CF, Lee CK. The risks for ovarian, endometrial, breast, colorectal, and other cancers in women with newly diagnosed endometriosis or adenomyosis: a population-based study. Int J Gynecol Cancer. 2015; 25: 968–976. https://doi.org/10.1097/IGC.0000000000000454 - 3Zeng H, Wang Y. Effects of various controlled ovarian hyperstimulation protocols and surgery on pregnancy outcomes in women with endometriosis. Gynecol Endocrinol. 2024; 40:2381504. https://doi.org/10.1080/09513590.2024.2381504 - 4Xu B, Guo N, Zhang XM, Shi W, Tong XH, Iqbal F, et al. Oocyte quality is decreased in women with minimal or mild endometriosis. Sci rep. 2015; 5:10779. https://doi.org/10.1038/srep10779 - 5Ducreux B, Patrat C, Trasler J, Fauque P. Transcriptomic integrity of human oocytes used in ARTs: technical and intrinsic factor effects. Hum Reprod Update. 2024; 30: 26–47. https://doi.org/10.1093/humupd/dmad025 - 6Ashrafi M, Arabipoor A, Hemat M, Salman-Yazdi R. The impact of the localisation of endometriosis lesions on ovarian reserve and assisted reproduction techniques outcomes. J Obstet Gynaecol. 2019; 39: 91–97. https://doi.org/10.1080/01443615.2018.1465898 - 7Navarro J, Garrido N, Remohi J, Pellicer A. How does endometriosis affect infertility? Obstet Gynecol Clin North Am. 2003; 30: 181–192. https://doi.org/10.1016/s0889-8545(02)00060-8 - 8Harb HM, Gallos ID, Chu J, Harb M, Coomarasamy A. The effect of endometriosis on in vitro fertilisation outcome: a systematic review and meta-analysis. BJOG. 2013; 120: 1308–1320. https://doi.org/10.1111/1471-0528.12366 - 9Somigliana E, Li Piani L, Paffoni A, Salmeri N, Orsi M, Benaglia L, et al. Endometriosis and IVF treatment outcomes: unpacking the process. Reprod Biol Endocrinol. 2023; 21: 107. https://doi.org/10.1186/s12958-023-01157-8 - 10Toya M, Saito H, Ohta N, Saito T, Kaneko T, Hiroi M. Moderate and severe endometriosis is associated with alterations in the cell cycle of granulosa cells in patients undergoing in vitro fertilization and embryo transfer. Fertil Steril. 2000; 73: 344–350. https://doi.org/10.1016/s0015-0282(99)00507-5 - 11Lin X, Dai Y, Tong X, Xu W, Huang Q, Jin X, et al. Excessive oxidative stress in cumulus granulosa cells induced cell senescence contributes to endometriosis-associated infertility. Redox Biol. 2020; 30:101431. https://doi.org/10.1016/j.redox.2020.101431 - 12Ju W, Zhao Y, Yu Y, Zhao S, Xiang S, Lian F. Mechanisms of mitochondrial dysfunction in ovarian aging and potential interventions. Front Endocrinol. 2024; 15:1361289. https://doi.org/10.3389/fendo.2024.1361289 - 13Sasaki H, Hamatani T, Kamijo S, Iwai M, Kobanawa M, Ogawa S, et al. Impact of oxidative stress on age-associated decline in oocyte developmental competence. Front Endocrinol. 2019; 10:811. https://doi.org/10.3389/fendo.2019.00811 - 14De Wilde RL, Alvarez J, Brölmann H, Campo R, Cheong Y, Lundorff P, et al. Adhesions and endometriosis: challenges in subfertility management: (An expert opinion of the ANGEL-the ANti-adhesions in Gynaecology expert PaneL-group). Arch Gynecol Obstet. 2016; 294: 299–301. https://doi.org/10.1007/s00404-016-4049-2 - 15Sanchez AM, Vanni VS, Bartiromo L, Papaleo E, Zilberberg E, Candiani M, et al. Is the oocyte quality affected by endometriosis? A review of the literature. J Ovarian Res. 2017; 10: 43. https://doi.org/10.1186/s13048-017-0341-4 - 16Chantalat E, Valera MC, Vaysse C, Noirrit E, Rusidze M, Weyl A, et al. Estrogen receptors and endometriosis. Int J Mol Sci. 2020; 21:2815. https://doi.org/10.3390/ijms21082815 - 17Miller JE, Ahn SH, Monsanto SP, Khalaj K, Koti M, Tayade C. Implications of immune dysfunction on endometriosis associated infertility. Oncotarget. 2017; 8: 7138–7147. https://doi.org/10.18632/oncotarget.12577 - 18Ahn SH, Monsanto SP, Miller C, Singh SS, Thomas R, Tayade C. Pathophysiology and immune dysfunction in endometriosis. Biomed Res Int. 2015; 2015:795976. https://doi.org/10.1155/2015/795976 - 19Fekri S, Makoui RH, Ansari N, Makoui MH. Correlation between the existence of serum autoantibodies and the risk of endometriosis: a systematic review and meta-analysis. Turk J Obstet Gynecol. 2024; 21: 104–117. https://doi.org/10.4274/tjod.galenos.2024.77489 - 20Cecchino GN, Seli E, Alves da Motta EL, García-Velasco JA. The role of mitochondrial activity in female fertility and assisted reproductive technologies: overview and current insights. Reprod Biomed Online. 2018; 36: 686–697. https://doi.org/10.1016/j.rbmo.2018.02.007 - 21Chen 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 - 22Atkins HM, Bharadwaj MS, O'Brien Cox A, Furdui CM, Appt SE, Caudell DL. Endometrium and endometriosis tissue mitochondrial energy metabolism in a nonhuman primate model. Reprod Biol Endocrinol. 2019; 17: 70. https://doi.org/10.1186/s12958-019-0513-8 - 23Kobayashi 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: 2783–2791. https://doi.org/10.1111/jog.15791 - 24Creed J, Maggrah A, Reguly B, Harbottle A. Mitochondrial DNA deletions accurately detect endometriosis in symptomatic females of child-bearing age. Biomark Med. 2019; 13: 291–306. https://doi.org/10.2217/bmm-2018-0419 - 25Babayev E, Seli E. Oocyte mitochondrial function and reproduction. Curr Opin Obstet Gynecol. 2015; 27: 175–181. https://doi.org/10.1097/GCO.0000000000000164 - 26Kaltsas A, Zikopoulos A, Moustakli E, Zachariou A, Tsirka G, Tsiampali C, et al. The silent threat to Women's fertility: uncovering the devastating effects of oxidative stress. Antioxidants. 2023; 12:1490. https://doi.org/10.3390/antiox12081490 - 27Seino T, Saito H, Kaneko T, Takahashi T, Kawachiya S, Kurachi H. Eight-hydroxy-2′-deoxyguanosine in granulosa cells is correlated with the quality of oocytes and embryos in an in vitro fertilization-embryo transfer program. Fertil Steril. 2002; 77: 1184–1190. https://doi.org/10.1016/s0015-0282(02)03103-5 - 28Wyatt J, Fernando SM, Powell SG, Hill CJ, Arshad I, Probert C, et al. The role of iron in the pathogenesis of endometriosis: a systematic review. Hum Reprod Open. 2023; 2023:hoad033. https://doi.org/10.1093/hropen/hoad033 - 29Karuputhula NB, Chattopadhyay R, Chakravarty B, Chaudhury K. Oxidative status in granulosa cells of infertile women undergoing IVF. Syst Biol Reprod Med. 2013; 59: 91–98. https://doi.org/10.3109/19396368.2012.743197 - 30Nishihara T, Matsumoto K, Hosoi Y, Morimoto Y. Evaluation of antioxidant status and oxidative stress markers in follicular fluid for human in vitro fertilization outcome. Reprod Med Biol. 2018; 17: 481–486. https://doi.org/10.1002/rmb2.12229 - 31Clavero A, Castilla JA, Núñez AI, García-Peña ML, Maldonado V, Fontes J. Apoptosis in human granulosa cells after induction of ovulation in women participating in an intracytoplasmic sperm injection program. Eur J Obstet Gynecol Reprod Biol. 2003; 110: 181–185. https://doi.org/10.1016/s0301-2115(03)00243-4 - 32Albertini DF, Barrett SL. Oocyte-somatic cell communication. Reprod Suppl. 2003; 61: 49–54. - 33Adashi EY. Endocrinology of the ovary. Hum Reprod. 1994; 9: 815–827. https://doi.org/10.1093/oxfordjournals.humrep.a138602 - 34Ávila J, González-Fernández R, Rotoli D, Hernández J, Palumbo A. Oxidative stress in granulosa-lutein cells from in vitro fertilization patients. Reprod Sci. 2016; 23: 1656–1661. https://doi.org/10.1177/1933719116674077 - 35Nakahara K, Saito H, Saito T, Ito M, Ohta N, Sakai N, et al. Incidence of apoptotic bodies in membrane granulosa of the patients participating in an in vitro fertilization program. Fertil Steril. 1997; 67: 302–308. https://doi.org/10.1016/S0015-0282(97)81915-2 - 36Da Broi MG, Jordão AA Jr, Ferriani RA, Navarro PA. Oocyte oxidative DNA damage may be involved in minimal/mild endometriosis-related infertility. Mol Reprod Dev. 2018; 85: 128–136. https://doi.org/10.1002/mrd.22943 - 37Agarwal A, Maldonado Rosas I, Anagnostopoulou C, Cannarella R, Boitrelle F, Munoz LV, et al. Oxidative stress and assisted reproduction: a comprehensive review of its pathophysiological role and strategies for optimizing embryo culture environment. Antioxidants. 2022; 11:477. https://doi.org/10.3390/antiox11030477 - 38Creed JM, Maggrah A, Usher R, Desa E, Harbottle A. How can mitochondrial DNA deletions act as a biomarker for the detection of endometriosis within the clinic? Biomark Med. 2020; 14: 5–8. https://doi.org/10.2217/bmm-2019-0435 - 39D'Erchia AM, Atlante A, Gadaleta G, Pavesi G, Chiara M, De Virgilio C, et al. Tissue-specific mtDNA abundance from exome data and its correlation with mitochondrial transcription, mass and respiratory activity. Mitochondrion. 2015; 20: 13–21. https://doi.org/10.1016/j.mito.2014.10.005 - 40Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet. 2005; 6: 389–402. https://doi.org/10.1038/nrg1606 - 41Zhou 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. 2024; 65: 211–226. https://doi.org/10.1016/j.jare.2023.11.033 - 42Itsara LS, Kennedy SR, Fox EJ, Yu S, Hewitt JJ, Sanchez-Contreras M, et al. Oxidative stress is not a major contributor to somatic mitochondrial DNA mutations. PLoS Genet. 2014; 10:e1003974. https://doi.org/10.1371/journal.pgen.1003974 - 43Gammage PA, Frezza C. Mitochondrial DNA: the overlooked oncogenome? BMC Biol. 2019; 17: 53. https://doi.org/10.1186/s12915-019-0668-y - 44Goud PT, Goud AP, Joshi N, Puscheck E, Diamond MP, Abu-Soud HM. Dynamics of nitric oxide, altered follicular microenvironment, and oocyte quality in women with endometriosis. Fertil Steril. 2014; 102: 151–159.e5. https://doi.org/10.1016/j.fertnstert.2014.03.053 - 45Govatati S, Deenadayal M, Shivaji S, Bhanoori M. Mitochondrial displacement loop alterations are associated with endometriosis. Fertil Steril. 2013; 99: 1980–1986.e9. https://doi.org/10.1016/j.fertnstert.2013.02.021 - 46Kobayashi H, Imanaka S, Nakamura H, Tsuji A. Understanding the role of epigenomic, genomic and genetic alterations in the development of endometriosis (review). Mol Med rep. 2014; 9: 1483–1505. https://doi.org/10.3892/mmr.2014.2057 - 47Cho S, Lee YM, Choi YS, Yang HI, Jeon YE, Lee KE, et al. Mitochondria DNA polymorphisms are associated with susceptibility to endometriosis. DNA Cell Biol. 2012; 31: 317–322. https://doi.org/10.1089/dna.2011.1279 - 48Mansour G, Sharma RK, Agarwal A, Falcone T. Endometriosis-induced alterations in mouse metaphase II oocyte microtubules and chromosomal alignment: a possible cause of infertility. Fertil Steril. 2010; 94: 1894–1899. https://doi.org/10.1016/j.fertnstert.2009.09.043 - 49Rajani S, Chattopadhyay R, Goswami SK, Ghosh S, Sharma S, Chakravarty B. Assessment of oocyte quality in polycystic ovarian syndrome and endometriosis by spindle imaging and reactive oxygen species levels in follicular fluid and its relationship with IVF-ET outcome. J Hum Reprod Sci. 2012; 5: 187–193. https://doi.org/10.4103/0974-1208.101020 - 50Huo P, Zhang N, Zhang P, Wu X. The levels of follicular fluid cell-free mitochondrial DNA could serve as a biomarker for pregnancy success in patients with small ovarian endometriosis cysts: a case-control study. Medicine. 2020; 99:e23348. https://doi.org/10.1097/MD.0000000000023348 - 51May-Panloup P, Chretien MF, Malthiery Y, Reynier P. Mitochondrial DNA in the oocyte and the developing embryo. Curr Top Dev Biol. 2007; 77: 51–83. https://doi.org/10.1016/S0070-2153(06)77003-X - 52Garrido N, Pellicer A, Remohí J, Simón C. Uterine and ovarian function in endometriosis. Semin Reprod Med. 2003; 21: 183–192. https://doi.org/10.1055/s-2003-41325 - 53Cogliati S, Cabrera-Alarcón JL, Enriquez JA. Regulation and functional role of the electron transport chain supercomplexes. Biochem Soc Trans. 2021; 49: 2655–2668. https://doi.org/10.1042/BST20210460 - 54Hsu AL, Townsend PM, Oehninger S, Castora FJ. Endometriosis may be associated with mitochondrial dysfunction in cumulus cells from subjects undergoing in vitro fertilization-intracytoplasmic sperm injection, as reflected by decreased adenosine triphosphate production. Fertil Steril. 2015; 103: 347–352.e1. https://doi.org/10.1016/j.fertnstert.2014.11.002 - 55Van Blerkom J. Mitochondria as regulatory forces in oocytes, preimplantation embryos and stem cells. Reprod Biomed Online. 2008; 16: 553–569. https://doi.org/10.1016/s1472-6483(10)60463-4 - 56El Shourbagy SH, Spikings EC, Freitas M, St John JC. Mitochondria directly influence fertilisation outcome in the pig. Reproduction. 2006; 131: 233–245. https://doi.org/10.1530/rep.1.00551 - 57Kao SH, Huang HC, Hsieh RH, Chen SC, Tsai MC, Tzeng CR. Oxidative damage and mitochondrial DNA mutations with endometriosis. Ann N Y Acad Sci. 2005; 1042: 186–194. https://doi.org/10.1196/annals.1338.021 - 58Harbottle A, Maggrah A, Usher R, Desa E, Creed JM. A novel 8.7-kb mitochondrial genome deletion accurately detects endometriosis in the plasma of symptomatic women. Biomark Med. 2020; 14: 97–107. https://doi.org/10.2217/bmm-2019-0451 - 59Li X, Ji D, Marley JL, Zou W, Deng X, Cao Y, et al. Association between mitochondrial DNA D-loop region polymorphisms and endometriosis in a Chinese population. J Assist Reprod Genet. 2020; 37: 2171–2179. https://doi.org/10.1007/s10815-020-01853-z - 60Andres MP, Cardena MMSG, Fridman C, Podgaec S. Polymorphisms of mitochondrial DNA control region are associated to endometriosis. J Assist Reprod Genet. 2018; 35: 533–538. https://doi.org/10.1007/s10815-017-1082-4 - 61Govatati S, Tipirisetti NR, Perugu S, Kodati VL, Deenadayal M, Satti V, et al. Mitochondrial genome variations in advanced stage endometriosis: a study in south Indian population. PLoS One. 2012; 7:e40668. https://doi.org/10.1371/journal.pone.0040668 - 62Foury F, Hu J, Vanderstraeten S. Mitochondrial DNA mutators. Cell Mol Life Sci. 2004; 61: 2799–2811. https://doi.org/10.1007/s00018-004-4220-y - 63Gohil D, Sarker AH, Roy R. Base excision repair: mechanisms and impact in biology, disease, and medicine. Int J Mol Sci. 2023; 24:14186. https://doi.org/10.3390/ijms241814186 - 64Stewart JB, Chinnery PF. The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat Rev Genet. 2015; 16: 530–542. https://doi.org/10.1038/nrg3966 - 65Kobayashi H, Shigetomi H, Imanaka S. Nonhormonal therapy for endometriosis based on energy metabolism regulation. Reprod Fertil. 2021; 2: C42–C57. https://doi.org/10.1530/RAF-21-0053 - 66Toniyan KA, Malkov AA, Biryukov NS, Gorbacheva EY, Boyarintsev VV, Ogneva IV. The cellular respiration of endometrial biopsies from patients with various forms of endometriosis. Int J Mol Sci. 2024; 25:3680. https://doi.org/10.3390/ijms25073680 - 67Schon EA, DiMauro S, Hirano M, Gilkerson RW. Therapeutic prospects for mitochondrial disease. Trends Mol Med. 2010; 16: 268–276. https://doi.org/10.1016/j.molmed.2010.04.007 - 68Iyama T, Wilson DM 3rd. DNA repair mechanisms in dividing and non-dividing cells. DNA Repair. 2013; 12: 620–636. https://doi.org/10.1016/j.dnarep.2013.04.015 - 69Fontana GA, Gahlon HL. Mechanisms of replication and repair in mitochondrial DNA deletion formation. Nucleic Acids Res. 2020; 48: 11244–11258. https://doi.org/10.1093/nar/gkaa804 - 70Sulkshane P, Ram J, Thakur A, Reis N, Kleifeld O, Glickman MH. Ubiquitination and receptor-mediated mitophagy converge to eliminate oxidation-damaged mitochondria during hypoxia. Redox Biol. 2021; 45:102047. https://doi.org/10.1016/j.redox.2021.102047 - 71Noren Hooten N, Kompaniez K, Barnes J, Lohani A, Evans MK. Poly(ADP-ribose) polymerase 1 (PARP-1) binds to 8-oxoguanine-DNA glycosylase (OGG1). J Biol Chem. 2011; 286: 44679–44690. https://doi.org/10.1074/jbc.M111.255869 - 72Kadam A, Jubin T, Roychowdhury R, Begum R. Role of PARP-1 in mitochondrial homeostasis. Biochim Biophys Acta Gen Subj. 2020; 1864:129669. https://doi.org/10.1016/j.bbagen.2020.129669 - 73Wang Y, An R, Umanah GK, Park H, Nambiar K, Eacker SM, et al. A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1. Science. 2016; 354:aad6872. https://doi.org/10.1126/science.aad6872 - 74Hong SJ, Dawson TM, Dawson VL. Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharmacol Sci. 2004; 25: 259–264. https://doi.org/10.1016/j.tips.2004.03.005 - 75Carvalho LF, Abrão MS, Biscotti C, Sharma R, Nutter B, Falcone T. Oxidative cell injury as a predictor of endometriosis progression. Reprod Sci. 2013; 20: 688–698. https://doi.org/10.1177/1933719112466301 - 76Farias JG, Zepeda A, Castillo R, Figueroa E, Ademoyero OT, Pulgar VM. Chronic hypobaric hypoxia diminishes the expression of base excision repair OGG1 enzymes in spermatozoa. Andrologia. 2018; 50. https://doi.org/10.1111/and.12876 - 77Kacperczyk-Bartnik J, Bartnik P, Goławski K, Sierdziński J, Mańka G, Kiecka M, et al. Plasma and peritoneal poly (ADP-ribose) polymerase levels in patients with endometriosis. Biomedicine. 2022; 10:2451. https://doi.org/10.3390/biomedicines10102451 - 78Belmonte B, Di Lorenzo G, Mangogna A, Bortot B, Bertolazzi G, Sammataro S, et al. PARP-1, EpCAM, and FRalpha as potential targets for intraoperative detection and delineation of endometriosis: a quantitative tissue expression analysis. Reprod Biol Endocrinol. 2024; 22: 92. https://doi.org/10.1186/s12958-024-01264-0 - 79Zhou Y, Zhao X, Zhang L, Xia Q, Peng Y, Zhang H, et al. Iron overload inhibits cell proliferation and promotes autophagy via PARP1/SIRT1 signaling in endometriosis and adenomyosis. Toxicology. 2022; 465:153050. https://doi.org/10.1016/j.tox.2021.153050 - 80Hsieh YY, Chang CC, Chen SY, Chen CP, Lin WH, Tsai FJ. XRCC1 399 Arg-related genotype and allele, but not XRCC1 His107Arg, XRCC1 Trp194Arg, KCNQ2, AT1R, and hOGG1 polymorphisms, are associated with higher susceptibility of endometriosis. Gynecol Endocrinol. 2012; 28: 305–309. https://doi.org/10.3109/09513590.2011.631624 - 81Lv MQ, Wang J, Yu XQ, Hong HH, Ren WJ, Ge P, et al. Association between x-ray repair cross-complementing group 1(XRCC1) Arg399Gln polymorphism and endometriosis: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2017; 218: 12–20. https://doi.org/10.1016/j.ejogrb.2017.09.011 - 82Wan X, Lai X, Huang M, Yu M, Ding T, Huang Z, et al. The role of mitochondrial DNA copy number in female infertility: a bidirectional two-sample mendelian randomization study. Gynecol Endocrinol. 2024; 40:2444380. https://doi.org/10.1080/09513590.2024.2444380 - 83Rozati R, Tabasum W, Mehdi AG, Ayapati VA, Khan AA, Ahmed TN, et al. The impact of mitochondrial dysfunction in human oocytes on embryo quality and conception rates in IVF patients with varying stages of endometriosis. Am J Med Clin Res Rev. 2025; 4: 1–14. 10.58372/2835-6276.1270Google Scholar - 84Máté G, Bernstein LR, Török AL. Endometriosis is a cause of infertility. Does reactive oxygen damage to gametes and embryos play a key role in the pathogenesis of infertility caused by endometriosis? Front Endocrinol. 2018; 9:725. https://doi.org/10.3389/fendo.2018.00725 - 85Ferreira FC, Teixeira J, Lidon F, Cagide F, Borges F, Pereira RMLN. Assisted reproduction technologies (ART): impact of mitochondrial (Dys)function and antioxidant therapy. Animals. 2025; 15:289. https://doi.org/10.3390/ani15030289 - 86Florou P, Anagnostis P, Theocharis P, Chourdakis M, Goulis DG. Does coenzyme Q10 supplementation improve fertility outcomes in women undergoing assisted reproductive technology procedures? A systematic review and meta-analysis of randomized-controlled trials. J Assist Reprod Genet. 2020; 37: 2377–2387. https://doi.org/10.1007/s10815-020-01906-3 - 87Pandey C, Maunder A, Liu J, Vaddiparthi V, Costello MF, Bahri-Khomami M, et al. The role of nutrient supplements in female infertility: An umbrella review and hierarchical evidence synthesis. Nutrients. 2024; 17:57. https://doi.org/10.3390/nu17010057 - 88Braun E. Mitochondrial replacement techniques for treating infertility. J Med Ethics. 2024: 1–9. https://doi.org/10.1136/jme-2023-109660 - 89Tesarik J, Mendoza-Tesarik R. Mitochondria in human fertility and infertility. Int J Mol Sci. 2023; 24:8950. https://doi.org/10.3390/ijms24108950 - 90Alegre GFS, Pastore GM. NAD+ precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR): potential dietary contribution to health. Curr Nutr Rep. 2023; 12: 445–464. https://doi.org/10.1007/s13668-023-00475-y - 91Zhou B, Zhao G, Zhu Y, Chen X, Zhang N, Yang J, et al. Protective effects of nicotinamide riboside on H(2)O(2)-induced oxidative damage in lens epithelial cells. Curr Eye Res. 2021; 46: 961–970. https://doi.org/10.1080/02713683.2020.1855662 - 92Wang L, Chen C, Zhou H, Tao L, Xu E. Nicotinamide riboside-driven modulation of SIRT3/mtROS/JNK signaling pathways alleviates myocardial ischemia-reperfusion injury. Int J Med Sci. 2024; 21: 2139–2148. https://doi.org/10.7150/ijms.97530 - 93Li H, Wang H, Xu J, Zeng X, Sun Y, Yang Q. Nicotinamide riboside supplementation ameliorated post-ovulatory oocyte quality decline. Reproduction. 2022; 165: 103–111. https://doi.org/10.1530/REP-22-0095 - 94Morris G, Walder KR, Berk M, Marx W, Walker AJ, Maes M, et al. The interplay between oxidative stress and bioenergetic failure in neuropsychiatric illnesses: can we explain it and can we treat it? Mol Biol rep. 2020; 47: 5587–5620. https://doi.org/10.1007/s11033-020-05590-5 - 95Zeng HF, Xu J, Wang XL, Li SJ, Han ZY. Nicotinamide mononucleotide alleviates heat stress-induced oxidative stress and apoptosis in BMECs through reducing mitochondrial damage and endoplasmic reticulum stress. Ecotoxicol Environ Saf. 2022; 235:113441. https://doi.org/10.1016/j.ecoenv.2022.113441 - 96Bertoldo MJ, Listijono DR, Ho WJ, Riepsamen AH, Goss DM, Richani D, et al. NAD+ repletion rescues female fertility during reproductive aging. Cell rep. 2020; 30: 1670–1681.e7. https://doi.org/10.1016/j.celrep.2020.01.058 - 97Velma GR, Krider IS, Alves ETM, Courey JM, Laham MS, Thatcher GRJ. Channeling nicotinamide Phosphoribosyltransferase (NAMPT) to address life and death. J Med Chem. 2024; 67: 5999–6026. https://doi.org/10.1021/acs.jmedchem.3c02112 - 98Pazzaglia S, Pioli C. Multifaceted role of PARP-1 in DNA repair and inflammation: pathological and therapeutic implications in cancer and non-cancer diseases. Cells. 2019; 9:41. https://doi.org/10.3390/cells9010041 - 99Oka SI, Byun J, Huang CY, Imai N, Ralda G, Zhai P, et al. Nampt potentiates antioxidant defense in diabetic cardiomyopathy. Circ Res. 2021; 129: 114–130. https://doi.org/10.1161/CIRCRESAHA.120.317943 - 100Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014; 24: 464–471. https://doi.org/10.1016/j.tcb.2014.04.002 - 101Sethi P, Mehan S, Khan Z, Maurya PK, Kumar N, Kumar A, et al. The SIRT-1/Nrf2/HO-1 axis: guardians of neuronal health in neurological disorders. Behav Brain Res. 2025; 476:115280. https://doi.org/10.1016/j.bbr.2024.115280 - 102Camacho-Pereira J, Tarragó MG, Chini CCS, Nin V, Escande C, Warner GM, et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 2016; 23: 1127–1139. https://doi.org/10.1016/j.cmet.2016.05.006 - 103Choi KH, Joo BS, Sun ST, Park MJ, Son JB, Joo JK, et al. Administration of visfatin during superovulation improves developmental competency of oocytes and fertility potential in aged female mice. Fertil Steril. 2012; 97: 1234–1241.e1-3. https://doi.org/10.1016/j.fertnstert.2012.02.032 - 104Park BK, Park MJ, Kim HG, Han SE, Kim CW, Joo BS, et al. Role of Visfatin in restoration of ovarian aging and fertility in the mouse aged 18 months. Reprod Sci. 2020; 27: 681–689. https://doi.org/10.1007/s43032-019-00074-9 - 105Guo C, Huang Q, Wang Y, Yao Y, Li J, Chen J, et al. Therapeutic application of natural products: NAD+ metabolism as potential target. Phytomedicine. 2023; 114:154768. https://doi.org/10.1016/j.phymed.2023.154768 - 106Li YR, Li S, Lin CC. Effect of resveratrol and pterostilbene on aging and longevity. Biofactors. 2018; 44: 69–82. https://doi.org/10.1002/biof.1400 - 107Ungurianu A, Zanfirescu A, Margină D. Sirtuins, resveratrol and the intertwining cellular pathways connecting them. Ageing Res Rev. 2023; 88:101936. https://doi.org/10.1016/j.arr.2023.101936 - 108Escande C, Nin V, Price NL, Capellini V, Gomes AP, Barbosa MT, et al. Flavonoid apigenin is an inhibitor of the NAD+ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes. 2013; 62: 1084–1093. https://doi.org/10.2337/db12-1139 - 109Chong MC, Silva A, James PF, Wu SSX, Howitt J. Exercise increases the release of NAMPT in extracellular vesicles and alters NAD(+) activity in recipient cells. Aging Cell. 2022; 21:e13647. https://doi.org/10.1111/acel.13647 - 110Di Emidio G, Vergara T, Konstantinidou F, Flati I, Stuppia L, Artini PG, et al. NAD(+) metabolism and mitochondrial activity in the aged oocyte: focus on the effects of NAMPT stimulation. Aging Dis. 2024; 15: 2828–2851. https://doi.org/10.14336/AD.2024.0241 - 111Vašková J, Klepcová Z, Špaková I, Urdzík P, Štofilová J, Bertková I, et al. The importance of natural antioxidants in female reproduction. Antioxidants. 2023; 12:907. https://doi.org/10.3390/antiox12040907 - 112Sosa F, Romo S, Kjelland ME, Álvarez-Gallardo H, Pérez-Reynozo S, Urbán-Duarte D, et al. Effect of pterostilbene on development, equatorial lipid accumulation and reactive oxygen species production of in vitro-produced bovine embryos. Reprod Domest Anim. 2020; 55: 1490–1500. https://doi.org/10.1111/rda.13798 - 113Pollard CL, Gibb Z, Hawdon A, Swegen A, Grupen CG. Supplementing media with NAD(+) precursors enhances the in vitro maturation of porcine oocytes. J Reprod Dev. 2021; 67: 319–326. https://doi.org/10.1262/jrd.2021-080 - 114Kang BE, Choi JY, Stein S, Ryu D. Implications of NAD(+) boosters in translational medicine. Eur J Clin Invest. 2020; 50:e13334. https://doi.org/10.1111/eci.13334 - 115Villalba JM, Alcaín FJ. Sirtuin activators and inhibitors. Biofactors. 2012; 38: 349–359. https://doi.org/10.1002/biof.1032 - 116Sasaki Y, Zhu J, Shi Y, Gu W, Kobe B, Ve T, et al. Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection. Exp Neurol. 2021; 345:113842. https://doi.org/10.1016/j.expneurol.2021.113842 - 117Bochum S, Berger S, Martens UM. Olaparib. Recent Results Cancer Res. 2018; 211: 217–233. https://doi.org/10.1007/978-3-319-91442-8_15 - 118Krainz T, Lamade AM, Du L, Maskrey TS, Calderon MJ, Watkins SC, et al. Synthesis and evaluation of a mitochondria-targeting poly(ADP-ribose) Polymerase-1 inhibitor. ACS Chem Biol. 2018; 13: 2868–2879. https://doi.org/10.1021/acschembio.8b00423 - 119Pollard CL, Gibb Z, Swegen A, Grupen CG. NAD(+), Sirtuins and PARPs: enhancing oocyte developmental competence. J Reprod Dev. 2022; 68: 345–354. https://doi.org/10.1262/jrd.2022-052 - 120Kim DH, Lee HR, Kim MG, Lee JS, Jin SJ, Lee HT. The effect of poly(ADP-ribosyl)ation inhibition on the porcine cumulus-oocyte complex during in vitro maturation. Biochem Biophys Res Commun. 2017; 483: 752–758. https://doi.org/10.1016/j.bbrc.2016.12.070 - 121Peclat TR, Thompson KL, Warner GM, Chini CCS, Tarragó MG, Mazdeh DZ, et al. CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell. 2022; 21:e13589. https://doi.org/10.1111/acel.13589 - 122Figley MD, Gu W, Nanson JD, Shi Y, Sasaki Y, Cunnea K, et al. SARM1 is a metabolic sensor activated by an increased NMN/NAD(+) ratio to trigger axon degeneration. Neuron. 2021; 109: 1118–1136.e11. https://doi.org/10.1016/j.neuron.2021.02.009 - 123Wang Y, Pan ZN, Xing CH, Zhang HL, Sun SC. Nivalenol affects spindle formation and organelle functions during mouse oocyte maturation. Toxicol Appl Pharmacol. 2022; 436:115882. https://doi.org/10.1016/j.taap.2022.115882 Citing Literature Article Metrics Total unique accesses to an article’s full text in HTML or PDF/ePDF format.More metric information Scite metrics Explore this article's citation statements on scite.ai Share QR Code Generating QR code QR code copied to clipboard! Something went wrong while generating your QR code. Please try again in a moment. If the issue persists, refresh the page or contact support. Export citation Unable to load citation data. Please try again in a moment. How to cite Elkins, L. J., & Spiegelman, M. (2021). pyUserCalc: A revised Jupyter notebook calculator for uranium-series disequilibria in basalts. Earth and Space Science, 8, e2020EA001619. https://doi.org/10.1029/2020EA001619 Download Citation If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click on download. This feature enables you to download the bibliographic information (also called citation data, header data, or metadata) for the articles on our site. Citation manager file format Use the dropdown list to choose how to format the bibliographic data you're harvesting. Several citation manager formats are available, including EndNote and BibTex. You can then copy the formatted citation (as displayed) or download it as file, to your device. If the RefWorks format is chosen, the 'Download' button will be replaced with an option to directly export to RefWorks