PMID- 38383507 OWN - NLM STAT- MEDLINE DCOM- 20240223 LR - 20240224 IS - 2041-4889 (Electronic) VI - 15 IP - 2 DP - 2024 Feb 21 TI - Advanced oxidation protein products attenuate the autophagy-lysosome pathway in ovarian granulosa cells by modulating the ROS-dependent mTOR-TFEB pathway. PG - 161 LID - 10.1038/s41419-024-06540-w [doi] LID - 161 AB - Oxidative stress dysfunction has recently been found to be involved in the pathogenesis of premature ovarian insufficiency (POI). Previously, we found that advanced oxidation protein products (AOPPs) in plasma were elevated in women with POI and had an adverse effect on granulosa cell proliferation. However, the mechanism underlying the effects of AOPPs on autophagy-lysosome pathway regulation in granulosa cells remains unclear. In this study, the effect of AOPPs on autophagy and lysosomal biogenesis and the underlying mechanisms were explored by a series of in vitro experiments in KGN and COV434 cell lines. AOPP-treated rat models were employed to determine the negative effect of AOPPs on the autophagy-lysosome systems in vivo. We found that increased AOPP levels activated the mammalian target of rapamycin (mTOR) pathway, and inhibited the autophagic response and lysosomal biogenesis in KGN and COV434 cells. Furthermore, scavenging of reactive oxygen species (ROS) with N-acetylcysteine and blockade of the mTOR pathway with rapamycin or via starvation alleviated the AOPP-induced inhibitory effects on autophagy and lysosomal biogenesis, suggesting that these effects of AOPPs are ROS-mTOR dependent. The protein expression and nuclear translocation of transcription factor EB (TFEB), the key regulator of lysosomal and autophagic function, were also impaired by the AOPP-activated ROS-mTOR pathway. In addition, TFEB overexpression attenuated the AOPP-induced impairment of autophagic flux and lysosomal biogenesis in KGN and COV434 cells. Chronic AOPP stimulation in vivo also impaired autophagy and lysosomal biogenesis in granulosa cells of rat ovaries. The results highlight that AOPPs lead to impairment of autophagic flux and lysosomal biogenesis via ROS-mTOR-TFEB signaling in granulosa cells and participate in the pathogenesis of POI. CI - (c) 2024. The Author(s). FAU - Zhou, Xing-Yu AU - Zhou XY AD - Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, PR China. FAU - Lai, Yun-Hui AU - Lai YH AD - Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, PR China. FAU - Zhang, Jun AU - Zhang J AD - Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, PR China. FAU - Li, Ying AU - Li Y AD - Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, PR China. FAU - Wu, Xiao-Min AU - Wu XM AD - Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, PR China. FAU - Yang, Yi-Zhen AU - Yang YZ AD - Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, PR China. FAU - Zhang, Xiao-Fei AU - Zhang XF AD - Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, PR China. FAU - Ma, Lin-Zi AU - Ma LZ AD - Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, PR China. FAU - Zheng, Ke-Ming AU - Zheng KM AD - Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, PR China. FAU - Liu, Yu-Dong AU - Liu YD AD - Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, PR China. FAU - Wang, Zhe AU - Wang Z AD - Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, PR China. FAU - Chen, Shi-Ling AU - Chen SL AUID- ORCID: 0000-0003-4473-5538 AD - Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, PR China. chensl_92@163.com. LA - eng GR - 2022M711523/China Postdoctoral Science Foundation/ GR - 82201794/National Natural Science Foundation of China (National Science Foundation of China)/ GR - 81901559/National Natural Science Foundation of China (National Science Foundation of China)/ PT - Journal Article DEP - 20240221 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Advanced Oxidation Protein Products) RN - 0 (Reactive Oxygen Species) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors) RN - 0 (TFEB protein, human) RN - EC 2.7.1.1 (mTOR protein, rat) RN - 0 (TFEB protein, rat) SB - IM MH - Humans MH - Rats MH - Female MH - Animals MH - *Advanced Oxidation Protein Products/metabolism/pharmacology MH - Reactive Oxygen Species/metabolism MH - *TOR Serine-Threonine Kinases/metabolism MH - Autophagy MH - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism MH - Lysosomes/metabolism MH - Granulosa Cells/metabolism MH - Mammals PMC - PMC10881514 COIS- The authors declare no competing interests. EDAT- 2024/02/22 00:43 MHDA- 2024/02/23 06:42 PMCR- 2024/02/21 CRDT- 2024/02/21 23:43 PHST- 2023/03/16 00:00 [received] PHST- 2024/02/05 00:00 [accepted] PHST- 2024/02/02 00:00 [revised] PHST- 2024/02/23 06:42 [medline] PHST- 2024/02/22 00:43 [pubmed] PHST- 2024/02/21 23:43 [entrez] PHST- 2024/02/21 00:00 [pmc-release] AID - 10.1038/s41419-024-06540-w [pii] AID - 6540 [pii] AID - 10.1038/s41419-024-06540-w [doi] PST - epublish SO - Cell Death Dis. 2024 Feb 21;15(2):161. doi: 10.1038/s41419-024-06540-w.