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Autophagy plays a crucial role in maintaining organ homeostasis, and age-related upregulation of the autophagy inhibitor protein, Rubicon, has been linked to cellular and tissue dysfunction. This review describes how granulosa cell autophagy supports follicular growth and oocyte selection and maturation by regulating cellular energy metabolism and protein quality control. We then introduce the role of selective autophagy, including mitophagy or lipophagy, in steroidogenesis and cellular remodeling during luteinization. In aged ovaries, Rubicon accumulation suppresses autophagic flux, leading to diminished oxidative-stress resilience and enhanced DNA damage. Moreover, impaired autophagy drives the accumulation of ATP citrate lyase, which correlates with poor oocyte quality and reduced ovarian reserve. Following fertilization, oocytes further upregulate autophagy to provide the energy required for blastocyst transition. Conversely, in infertility-related disorders, such as premature ovarian insufficiency, endometriosis, and polycystic ovary syndrome, either deficient or excessive autophagy contributes to disease pathogenesis. Both autophagy inhibitors (e.g., Rubicon) and activators (e.g., Beclin1) could be emerging as promising biomarkers for assessing ovarian autophagy status. Therapeutically, Rubicon inhibition by trehalose in aged ovaries and autophagy suppression by agents such as hydroxychloroquine in polycystic ovary syndrome and endometriosis hold potential. Establishing robust methods to evaluate ovarian autophagy will be essential for translating these insights into targeted treatments.<\/jats:p>","DOI":"10.3390\/antiox14080919","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T14:50:03Z","timestamp":1753714203000},"page":"919","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Interplay of Oxidative Stress, Autophagy, and Rubicon in Ovarian Follicle Dynamics: Orchestrating Ovarian Aging"],"prefix":"10.3390","volume":"14","author":[{"given":"Kiyotaka","family":"Yamada","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1577-1890","authenticated-orcid":false,"given":"Masami","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruka","family":"Nunomura","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Nishigori","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Furuta","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihoko","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akemi","family":"Yamaki","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanto","family":"Shozu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ippei","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayaka","family":"Tsuda","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Shima","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2861-2183","authenticated-orcid":false,"given":"Akitoshi","family":"Nakashima","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wallace, W.H., and Kelsey, T.W. (2010). Human ovarian reserve from conception to the menopause. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0008772"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e20230175","DOI":"10.1590\/1806-9282.20230175","article-title":"Granulosa cells and follicular development: A brief review","volume":"69","author":"Cavalcanti","year":"2023","journal-title":"Rev. Assoc. Med. Bras. (1992)"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.1016\/j.ajpath.2018.07.021","article-title":"Trophoblast-Specific Conditional Atg7 Knockout Mice Develop Gestational Hypertension","volume":"188","author":"Aoki","year":"2018","journal-title":"Am. J. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103766","DOI":"10.1016\/j.jri.2022.103766","article-title":"Chloroquine is a safe autophagy inhibitor for sustaining the expression of antioxidant enzymes in trophoblasts","volume":"155","author":"Furuta","year":"2023","journal-title":"J. Reprod. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1080\/15548627.2019.1707494","article-title":"Evidence for lysosomal biogenesis proteome defect and impaired autophagy in preeclampsia","volume":"16","author":"Nakashima","year":"2020","journal-title":"Autophagy"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"303","DOI":"10.4161\/auto.22927","article-title":"Impaired autophagy by soluble endoglin, under physiological hypoxia in early pregnant period, is involved in poor placentation in preeclampsia","volume":"9","author":"Nakashima","year":"2013","journal-title":"Autophagy"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"110792","DOI":"10.1016\/j.mce.2020.110792","article-title":"Inhibition of autophagy in theca cells induces CYP17A1 and PAI-1 expression via ROS\/p38 and JNK signalling during the development of polycystic ovary syndrome","volume":"508","author":"Kobayashi","year":"2020","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Yamada, K., Ito, M., Nunomura, H., Nishigori, T., Furuta, A., Yoshida, M., Yamaki, A., Nakamura, T., Iwase, A., and Shima, T. (2025). Rubicon, a Key Molecule for Oxidative Stress-Mediated DNA Damage, in Ovarian Granulosa Cells. Antioxidants, 14.","DOI":"10.3390\/antiox14040470"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5720","DOI":"10.1093\/emboj\/19.21.5720","article-title":"LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing","volume":"19","author":"Kabeya","year":"2000","journal-title":"EMBO J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/nrn3961","article-title":"Compromised autophagy and neurodegenerative diseases","volume":"16","author":"Menzies","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Minami, S., Nakamura, S., and Yoshimori, T. (2021). Rubicon in Metabolic Diseases and Ageing. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.816829"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"102428","DOI":"10.1016\/j.arr.2024.102428","article-title":"Autophagy in aging-related diseases and cancer: Principles, regulatory mechanisms and therapeutic potential","volume":"100","author":"Wu","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1038\/sj.emboj.7601623","article-title":"Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4","volume":"26","author":"Shvets","year":"2007","journal-title":"EMBO J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/ncb1846","article-title":"Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages","volume":"11","author":"Matsunaga","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1038\/ncb1854","article-title":"Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex","volume":"11","author":"Zhong","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1038\/s41467-019-08729-6","article-title":"Suppression of autophagic activity by Rubicon is a signature of aging","volume":"10","author":"Nakamura","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Yamamuro, T., Nakamura, S., Yamano, Y., Endo, T., Yanagawa, K., Tokumura, A., Matsumura, T., Kobayashi, K., Mori, H., and Enokidani, Y. (2021). Rubicon prevents autophagic degradation of GATA4 to promote Sertoli cell function. PLoS Genet., 17.","DOI":"10.1371\/journal.pgen.1009688"},{"key":"ref_18","first-page":"200","article-title":"Initial and cyclic recruitment of ovarian follicles","volume":"21","author":"McGee","year":"2000","journal-title":"Endocr. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1002\/rmb2.12292","article-title":"Interaction between growing oocytes and granulosa cells in vitro","volume":"19","author":"Alam","year":"2020","journal-title":"Reprod. Med. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1093\/oxfordjournals.humrep.a136650","article-title":"Inhibin","volume":"3","author":"McNeilly","year":"1988","journal-title":"Hum. Reprod."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Dompe, C., Kulus, M., Stefanska, K., Kranc, W., Chermula, B., Bryl, R., Pienkowski, W., Nawrocki, M.J., Petitte, J.N., and Stelmach, B. (2021). Human Granulosa Cells-Stemness Properties, Molecular Cross-Talk and Follicular Angiogenesis. Cells, 10.","DOI":"10.3390\/cells10061396"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"C880","DOI":"10.1152\/ajpcell.00277.2002","article-title":"Functional analysis of gap junctions in ovarian granulosa cells: Distinct role for connexin43 in early stages of folliculogenesis","volume":"284","author":"Gittens","year":"2003","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2532","DOI":"10.1016\/j.fertnstert.2009.11.021","article-title":"The role of autophagy in follicular development and atresia in rat granulosa cells","volume":"93","author":"Choi","year":"2010","journal-title":"Fertil. Steril."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1080\/15548627.2021.2005415","article-title":"Autophagy regulates differentiation of ovarian granulosa cells through degradation of WT1","volume":"18","author":"Shao","year":"2022","journal-title":"Autophagy"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1177\/0963689718797053","article-title":"In Vitro Derivation of Functional Sertoli-Like Cells from Mouse Embryonic Stem Cells","volume":"27","author":"Seol","year":"2018","journal-title":"Cell Transplant."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e3001","DOI":"10.1038\/cddis.2017.371","article-title":"Administration of follicle-stimulating hormone induces autophagy via upregulation of HIF-1\u03b1 in mouse granulosa cells","volume":"8","author":"Zhou","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Pan, Y., Wu, G., Chen, M., Lu, X., Shen, M., Li, H., and Liu, H. (2024). Lactate Promotes Hypoxic Granulosa Cells\u2019 Autophagy by Activating the HIF-1\u03b1\/BNIP3\/Beclin-1 Signaling Axis. Genes, 16.","DOI":"10.3390\/genes16010014"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1007\/s43032-022-01051-5","article-title":"BMP15 Modulates the H19\/miR-26b\/SMAD1 Axis Influences Yak Granulosa Cell Proliferation, Autophagy, and Apoptosis","volume":"30","author":"Yao","year":"2023","journal-title":"Reprod. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Alhelaisi, A., Alrezaki, A., Nahdi, S., Aldahmash, W., Alwasel, S., and Harrath, A.H. (2023). Early-Life Exposure to the Mycotoxin Fumonisin B1 and Developmental Programming of the Ovary of the Offspring: The Possible Role of Autophagy in Fertility Recovery. Toxics, 11.","DOI":"10.20944\/preprints202309.1557.v1"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e13374","DOI":"10.1111\/aji.13374","article-title":"Bone morphogenetic protein-2 enhances gonadotropin-independent follicular development via sphingosine kinase 1","volume":"85","author":"Ito","year":"2021","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"17848","DOI":"10.1073\/pnas.1908228116","article-title":"Cell phenotypic plasticity requires autophagic flux driven by YAP\/TAZ mechanotransduction","volume":"116","author":"Totaro","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s10456-020-09748-4","article-title":"BMP6\/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF","volume":"24","author":"Pulkkinen","year":"2021","journal-title":"Angiogenesis"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2961","DOI":"10.1038\/s41467-018-05388-x","article-title":"Contact inhibition controls cell survival and proliferation via YAP\/TAZ-autophagy axis","volume":"9","author":"Pavel","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.chom.2012.01.018","article-title":"Autophagy protein Rubicon mediates phagocytic NADPH oxidase activation in response to microbial infection or TLR stimulation","volume":"11","author":"Yang","year":"2012","journal-title":"Cell Host Microbe"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e3088","DOI":"10.1038\/cddis.2017.467","article-title":"miR-181a increases FoxO1 acetylation and promotes granulosa cell apoptosis via SIRT1 downregulation","volume":"8","author":"Zhang","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7215","DOI":"10.1038\/ncomms8215","article-title":"Acetylation of Beclin 1 inhibits autophagosome maturation and promotes tumour growth","volume":"6","author":"Sun","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"176339","DOI":"10.1016\/j.ejphar.2024.176339","article-title":"Quercetin activates autophagy to protect rats ovarian granulosa cells from H2O2-induced aging and injury","volume":"966","author":"Cai","year":"2024","journal-title":"Eur. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Casarini, L., and Crepieux, P. (2019). Molecular Mechanisms of Action of FSH. Front. Endocrinol., 10.","DOI":"10.3389\/fendo.2019.00305"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12435","DOI":"10.1073\/pnas.0603006103","article-title":"Follicle-stimulating hormone\/cAMP regulation of aromatase gene expression requires \u03b2-catenin","volume":"103","author":"Parakh","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1677\/JOE-06-0076","article-title":"Interplay of PI3K and cAMP\/PKA signaling, and rapamycin-hypersensitivity in TGF\u03b21 enhancement of FSH-stimulated steroidogenesis in rat ovarian granulosa cells","volume":"192","author":"Chen","year":"2007","journal-title":"J. Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1677\/joe.1.05550","article-title":"Progesterone secretion by luteinizing human granulosa cells: A possible cAMP-dependent but PKA-independent mechanism involved in its regulation","volume":"183","author":"Chin","year":"2004","journal-title":"J. Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"93","DOI":"10.5468\/ogs.2014.57.2.93","article-title":"Molecular mechanisms of luteinization","volume":"57","author":"Sugino","year":"2014","journal-title":"Obstet. Gynecol. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"E4194","DOI":"10.1073\/pnas.1409323111","article-title":"Beclin-1 deficiency in the murine ovary results in the reduction of progesterone production to promote preterm labor","volume":"111","author":"Gawriluk","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/s41419-023-05864-3","article-title":"Autophagy regulates sex steroid hormone synthesis through lysosomal degradation of lipid droplets in human ovary and testis","volume":"14","author":"Esmaeilian","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Liu, Q., Gao, H., Yang, F., Zhang, H., and Zeng, S. (2021). FSH Promotes Progesterone Synthesis by Enhancing Autophagy to Accelerate Lipid Droplet Degradation in Porcine Granulosa Cells. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.626927"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"10166","DOI":"10.1074\/jbc.M111.293274","article-title":"Follicle-stimulating hormone regulates pro-apoptotic protein Bcl-2-interacting mediator of cell death-extra long (BimEL)-induced porcine granulosa cell apoptosis","volume":"287","author":"Wang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"25310","DOI":"10.18632\/oncotarget.15813","article-title":"Oxidative stress-induced apoptosis in granulosa cells involves JNK, p53 and Puma","volume":"8","author":"Yang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1006\/dbio.2001.0269","article-title":"Mouse ovarian germ cell cysts undergo programmed breakdown to form primordial follicles","volume":"234","author":"Pepling","year":"2001","journal-title":"Dev. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6125","DOI":"10.1002\/jcp.27367","article-title":"Autophagy participates in cyst breakdown and primordial folliculogenesis by reducing reactive oxygen species levels in perinatal mouse ovaries","volume":"234","author":"Zhihan","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1038\/nature03029","article-title":"The role of autophagy during the early neonatal starvation period","volume":"432","author":"Kuma","year":"2004","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.devcel.2016.09.001","article-title":"Systemic Analysis of Atg5-Null Mice Rescued from Neonatal Lethality by Transgenic ATG5 Expression in Neurons","volume":"39","author":"Yoshii","year":"2016","journal-title":"Dev. Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1530\/REP-10-0489","article-title":"Autophagy is a cell survival program for female germ cells in the murine ovary","volume":"141","author":"Gawriluk","year":"2011","journal-title":"Reproduction"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e14338","DOI":"10.1111\/acel.14338","article-title":"Oocytes maintain low ROS levels to support the dormancy of primordial follicles","volume":"24","author":"Qin","year":"2025","journal-title":"Aging Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13024-019-0313-9","article-title":"Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis","volume":"14","author":"Beltran","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Labrador, L., Rodriguez, L., Beltran, S., Hernandez, F., Gomez, L., Ojeda, P., Bergmann, C., Calegaro-Nassif, M., Kerr, B., and Medinas, D.B. (2024). Overexpression of autophagy enhancer PACER\/RUBCNL in neurons accelerates disease in the SOD1G93A ALS mouse model. Biol. Res., 57.","DOI":"10.1186\/s40659-024-00567-1"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"eabc7409","DOI":"10.1126\/sciadv.abc7409","article-title":"Inhibition of the NLRP3 inflammasome prevents ovarian aging","volume":"7","author":"Muntane","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Leopardo, N.P., Velazquez, M.E., Cortasa, S., Gonzalez, C.R., and Vitullo, A.D. (2020). A dual death\/survival role of autophagy in the adult ovary of Lagostomus maximus (Mammalia-Rodentia). PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0232819"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.theriogenology.2023.02.021","article-title":"METTL3-mediated m6A methylation regulates granulosa cells autophagy during follicular atresia in pig ovaries","volume":"201","author":"Li","year":"2023","journal-title":"Theriogenology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.theriogenology.2024.06.024","article-title":"Autophagy is involved in granulosa cell death and follicular atresia in ewe ovaries","volume":"226","author":"Scudieri","year":"2024","journal-title":"Theriogenology"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Zheng, Y., Ma, L., Liu, N., Tang, X., Guo, S., Zhang, B., and Jiang, Z. (2019). Autophagy and Apoptosis of Porcine Ovarian Granulosa Cells During Follicular Development. Animals, 9.","DOI":"10.3390\/ani9121111"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/dvdy.21392","article-title":"Developmental expression of LC3\u03b1 and \u03b2: Absence of fibronectin or autophagy phenotype in LC3\u03b2 knockout mice","volume":"237","author":"Cann","year":"2008","journal-title":"Dev. Dyn."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e2205","DOI":"10.1038\/cddis.2016.93","article-title":"Tumor suppression in mice lacking GABARAP, an Atg8\/LC3 family member implicated in autophagy, is associated with alterations in cytokine secretion and cell death","volume":"7","author":"Salah","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/j.molcel.2015.11.019","article-title":"Structural Basis of the Differential Function of the Two C. elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy","volume":"60","author":"Wu","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"37204","DOI":"10.1074\/jbc.M113.528067","article-title":"Interaction of Bcl-2 with the autophagy-related GABAA receptor-associated protein (GABARAP): Biophysical characterization and functional implications","volume":"288","author":"Ma","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Shen, X.H., Jin, Y.X., Liang, S., Kwon, J.W., Zhu, J.W., Lei, L., and Kim, N.H. (2018). Autophagy is required for proper meiosis of porcine oocytes maturing in vitro. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-29872-y"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1038\/s41419-018-0368-5","article-title":"Role of autophagy in modulating post-maturation aging of mouse oocytes","volume":"9","author":"Lin","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Latorraca, L.B., Feitosa, W.B., Mariano, C., Moura, M.T., Fontes, P.K., Nogueira, M.F.G., and Paula-Lopes, F.F. (2020). Autophagy is a pro-survival adaptive response to heat shock in bovine cumulus-oocyte complexes. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-69939-3"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1126\/science.1154822","article-title":"Autophagy is essential for preimplantation development of mouse embryos","volume":"321","author":"Tsukamoto","year":"2008","journal-title":"Science"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Yamamoto, A., Mizushima, N., and Tsukamoto, S. (2014). Fertilization-induced autophagy in mouse embryos is independent of mTORC1. Biol. Reprod., 91.","DOI":"10.1095\/biolreprod.113.115816"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1126\/science.1210333","article-title":"Degradation of paternal mitochondria by fertilization-triggered autophagy in C. elegans embryos","volume":"334","author":"Sato","year":"2011","journal-title":"Science"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"E5261","DOI":"10.1073\/pnas.1605844113","article-title":"Autophagy and ubiquitin-proteasome system contribute to sperm mitophagy after mammalian fertilization","volume":"113","author":"Song","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1038\/s41419-020-03183-5","article-title":"Quercetin promotes in vitro maturation of oocytes from humans and aged mice","volume":"11","author":"Cao","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Chen, Y., Yang, J., and Zhang, L. (2023). The Impact of Follicular Fluid Oxidative Stress Levels on the Outcomes of Assisted Reproductive Therapy. Antioxidants, 12.","DOI":"10.3390\/antiox12122117"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2208","DOI":"10.1093\/humrep\/dead177","article-title":"Human ovarian aging is characterized by oxidative damage and mitochondrial dysfunction","volume":"38","author":"Smits","year":"2023","journal-title":"Hum. Reprod."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Huang, Y., Tu, M., Qian, Y., Ma, J., Chen, L., Liu, Y., Wu, Y., Chen, K., Liu, J., and Ying, Y. (2022). Age-Dependent Metabolomic Profile of the Follicular Fluids From Women Undergoing Assisted Reproductive Technology Treatment. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.818888"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1080\/15548627.2022.2063005","article-title":"Selective autophagic degradation of ACLY (ATP citrate lyase) maintains citrate homeostasis and promotes oocyte maturation","volume":"19","author":"He","year":"2023","journal-title":"Autophagy"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Quan, H., Guo, Y., Li, S., Jiang, Y., Shen, Q., He, Y., Zhou, X., Yuan, X., and Li, J. (2024). Phospholipid Phosphatase 3 (PLPP3) Induces Oxidative Stress to Accelerate Ovarian Aging in Pigs. Cells, 13.","DOI":"10.3390\/cells13171421"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Agarwal, A., Aponte-Mellado, A., Premkumar, B.J., Shaman, A., and Gupta, S. (2012). The effects of oxidative stress on female reproduction: A review. Reprod. Biol. Endocrinol., 10.","DOI":"10.1186\/1477-7827-10-49"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1172273","DOI":"10.1155\/2021\/1172273","article-title":"FOXO1 Is a Critical Switch Molecule for Autophagy and Apoptosis of Sow Endometrial Epithelial Cells Caused by Oxidative Stress","volume":"2021","author":"Lu","year":"2021","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.fertnstert.2008.05.016","article-title":"Melatonin and the ovary: Physiological and pathophysiological implications","volume":"92","author":"Tamura","year":"2009","journal-title":"Fertil. Steril."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Xu, G., Dong, Y., Wang, Z., Ding, H., Wang, J., Zhao, J., Liu, H., and Lv, W. (2023). Melatonin Attenuates Oxidative Stress-Induced Apoptosis of Bovine Ovarian Granulosa Cells by Promoting Mitophagy via SIRT1\/FoxO1 Signaling Pathway. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241612854"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.theriogenology.2021.08.028","article-title":"Involvement of PINK1\/Parkin-mediated mitophagy in mitochondrial functional disruption under oxidative stress in vitrified porcine oocytes","volume":"174","author":"Xu","year":"2021","journal-title":"Theriogenology"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1038\/s43587-023-00498-8","article-title":"Polyamine metabolite spermidine rejuvenates oocyte quality by enhancing mitophagy during female reproductive aging","volume":"3","author":"Zhang","year":"2023","journal-title":"Nat. Aging"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"172ra21","DOI":"10.1126\/scitranslmed.3004925","article-title":"Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans","volume":"5","author":"Titus","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1093\/biolre\/ioz160","article-title":"Ataxia-telangiectasia mutated coordinates the ovarian DNA repair and atresia-initiating response to phosphoramide mustard","volume":"102","author":"Clark","year":"2020","journal-title":"Biol. Reprod."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"eaax5819","DOI":"10.1126\/sciadv.aax5819","article-title":"CHK2-FOXK axis promotes transcriptional control of autophagy programs","volume":"6","author":"Chen","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13048-020-0615-0","article-title":"Decreased ovarian function and autophagy gene methylation in aging rats","volume":"13","author":"Li","year":"2020","journal-title":"J. Ovarian Res."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Tudorica, D.A., Basak, B., Puerta Cordova, A.S., Khuu, G., Rose, K., Lazarou, M., Holzbaur, E.L.F., and Hurley, J.H. (2024). A RAB7A phosphoswitch coordinates Rubicon Homology protein regulation of Parkin-dependent mitophagy. J. Cell Biol., 223.","DOI":"10.1083\/jcb.202309015"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.cell.2010.01.028","article-title":"Methods in mammalian autophagy research","volume":"140","author":"Mizushima","year":"2010","journal-title":"Cell"},{"key":"ref_90","first-page":"185","article-title":"BMP15 and GDF9 Gene Mutations in Premature Ovarian Failure","volume":"18","author":"Kumar","year":"2017","journal-title":"J. Reprod. Infertil."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Garcia-Ortiz, J.E., Pelosi, E., Omari, S., Nedorezov, T., Piao, Y., Karmazin, J., Uda, M., Cao, A., Cole, S.W., and Forabosco, A. (2009). Foxl2 functions in sex determination and histogenesis throughout mouse ovary development. BMC Dev. Biol., 9.","DOI":"10.1186\/1471-213X-9-36"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1038\/s41436-018-0287-y","article-title":"ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure","volume":"21","author":"Delcour","year":"2019","journal-title":"Genet. Med."},{"key":"ref_93","first-page":"844","article-title":"Melatonin regulates autophagy in granulosa cells from patients with premature ovarian insufficiency via activating Foxo3a","volume":"16","author":"Li","year":"2024","journal-title":"Aging"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.cmet.2007.11.001","article-title":"FoxO3 controls autophagy in skeletal muscle in vivo","volume":"6","author":"Mammucari","year":"2007","journal-title":"Cell Metab."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e23506","DOI":"10.1096\/fj.202302141R","article-title":"Anti-Mullerian hormone induces autophagy to preserve the primordial follicle pool in mice","volume":"38","author":"Boumerdassi","year":"2024","journal-title":"FASEB J."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1080\/15548627.2022.2094671","article-title":"Epg5 deficiency leads to primary ovarian insufficiency due to WT1 accumulation in mouse granulosa cells","volume":"19","author":"Liu","year":"2023","journal-title":"Autophagy"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"6634718","DOI":"10.1155\/2021\/6634718","article-title":"Advanced Oxidation Protein Products Induce G1\/G0-Phase Arrest in Ovarian Granulosa Cells via the ROS-JNK\/p38 MAPK-p21 Pathway in Premature Ovarian Insufficiency","volume":"2021","author":"Zhou","year":"2021","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/s41419-024-06540-w","article-title":"Advanced oxidation protein products attenuate the autophagy-lysosome pathway in ovarian granulosa cells by modulating the ROS-dependent mTOR-TFEB pathway","volume":"15","author":"Zhou","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"6182","DOI":"10.1210\/jc.2019-00780","article-title":"Gene Expression in Granulosa Cells From Small Antral Follicles From Women With or Without Polycystic Ovaries","volume":"104","author":"Owens","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1507\/endocrj.EJ21-0480","article-title":"Metformin ameliorates polycystic ovary syndrome in a rat model by decreasing excessive autophagy in ovarian granulosa cells via the PI3K\/AKT\/mTOR pathway","volume":"69","author":"Xu","year":"2022","journal-title":"Endocr. J."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1530\/JME-18-0198","article-title":"Gremlin, noggin, chordin and follistatin differentially modulate BMP-induced suppression of androgen secretion by bovine ovarian theca cells","volume":"62","author":"Glister","year":"2019","journal-title":"J. Mol. Endocrinol."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Gu, R., Dai, F., Xiang, C., Chen, J., Yang, D., Tan, W., Wang, Z., Liu, H., and Cheng, Y. (2023). BMP4 participates in the pathogenesis of PCOS by regulating glucose metabolism and autophagy in granulosa cells under hyperandrogenic environment. J. Steroid Biochem. Mol. Biol., 235.","DOI":"10.1016\/j.jsbmb.2023.106410"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"hoac009","DOI":"10.1093\/hropen\/hoac009","article-title":"ESHRE guideline: Endometriosis","volume":"2022","author":"Becker","year":"2022","journal-title":"Hum. Reprod. Open"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s00441-016-2428-4","article-title":"Increased concentration of 8-hydroxy-2\u2032-deoxyguanosine in follicular fluid of infertile women with endometriosis","volume":"366","author":"Cardoso","year":"2016","journal-title":"Cell Tissue Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1093\/molehr\/gaz066","article-title":"Activation of endoplasmic reticulum stress mediates oxidative stress-induced apoptosis of granulosa cells in ovaries affected by endometrioma","volume":"26","author":"Kunitomi","year":"2020","journal-title":"Mol. Hum. Reprod."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Lin, X., Dai, Y., Tong, X., Xu, W., Huang, Q., Jin, X., Li, C., Zhou, F., Zhou, H., and Lin, X. (2020). Excessive oxidative stress in cumulus granulosa cells induced cell senescence contributes to endometriosis-associated infertility. Redox Biol., 30.","DOI":"10.1016\/j.redox.2020.101431"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"bqac210","DOI":"10.1210\/endocr\/bqac210","article-title":"Decreased Expression of EZH2 in Granulosa Cells Contributes to Endometriosis-Associated Infertility by Targeting IL-1R2","volume":"164","author":"Lin","year":"2022","journal-title":"Endocrinology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.trsl.2020.06.013","article-title":"Induction of autophagy by Beclin-1 in granulosa cells contributes to follicular progesterone elevation in ovarian endometriosis","volume":"227","author":"Ding","year":"2021","journal-title":"Transl. Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1530\/JOE-13-0449","article-title":"Suppression of autophagic activation in the mouse uterus by estrogen and progesterone","volume":"221","author":"Choi","year":"2014","journal-title":"J. Endocrinol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1093\/biolre\/ioz234","article-title":"The autophagy protein, FIP200 (RB1CC1) mediates progesterone responses governing uterine receptivity and decidualization","volume":"102","author":"Oestreich","year":"2020","journal-title":"Biol. Reprod."},{"key":"ref_111","first-page":"479","article-title":"Targeting Estrogen Receptor Beta Ameliorates Diminished Ovarian Reserve via Suppression of the FOXO3a\/Autophagy Pathway","volume":"16","author":"Li","year":"2024","journal-title":"Aging Dis."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1093\/biolre\/ioac222","article-title":"Chemotherapy induced oxidative stress in the ovary: Drug-dependent mechanisms and potential interventions","volume":"108","author":"Trujillo","year":"2023","journal-title":"Biol. Reprod."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2242","DOI":"10.1210\/jc.2016-3723","article-title":"Premature Ovarian Insufficiency in Childhood Cancer Survivors: A Report From the St. Jude Lifetime Cohort","volume":"102","author":"Chemaitilly","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_114","first-page":"100279","article-title":"Circulating autophagy regulator Rubicon is linked to increased myocardial infarction risk","volume":"11","author":"Grazide","year":"2025","journal-title":"J. Mol. Cell Cardiol. Plus"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1191\/096120301678646137","article-title":"Hydroxychloroquine (HCQ) in lupus pregnancy: Double-blind and placebo-controlled study","volume":"10","author":"Levy","year":"2001","journal-title":"Lupus"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/14\/8\/919\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:16:59Z","timestamp":1760033819000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/14\/8\/919"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,27]]},"references-count":115,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["antiox14080919"],"URL":"https:\/\/doi.org\/10.3390\/antiox14080919","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,27]]}}}