PMID- 35087042 OWN - NLM STAT- MEDLINE DCOM- 20220408 LR - 20221022 IS - 2041-4889 (Electronic) VI - 13 IP - 1 DP - 2022 Jan 27 TI - Enhanced glycolysis in granulosa cells promotes the activation of primordial follicles through mTOR signaling. PG - 87 LID - 10.1038/s41419-022-04541-1 [doi] LID - 87 AB - In mammals, nonrenewable primordial follicles are activated in an orderly manner to maintain the longevity of reproductive life. Mammalian target of rapamycin (mTOR)-KIT ligand (KITL) signaling in pre-granulosa cells and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-forkhead Box O3a (FOXO3a) signaling in oocytes are important for primordial follicle activation. The activation process is accompanied by the enhancement of energy metabolism, but the causal relationship is unclear. In the present study, the levels of glycolysis-related proteins GLUT4, HK1, PFKL, and PKM2 were significantly increased in granulosa cells but were decreased in oocytes during the mouse primordial-to-primary follicle transition. Both short-term pyruvate deprivation in vitro and acute fasting in vivo increased the glycolysis-related gene and protein levels, decreased AMPK activity, and increased mTOR activity in mouse ovaries. The downstream pathways Akt and FOXO3a were phosphorylated, resulting in mouse primordial follicle activation. The blockade of glycolysis by 2-deoxyglucose (2-DG), but not the blockade of the communication network between pre-granulosa cells and oocyte by KIT inhibitor ISCK03, decreased short-term pyruvate deprivation-promoted mTOR activity. Glycolysis was also increased in human granulosa cells during the primordial-to-primary follicle transition, and short-term pyruvate deprivation promoted the activation of human primordial follicles by increasing the glycolysis-related protein levels and mTOR activity in ovarian tissues. Taken together, the enhanced glycolysis in granulosa cells promotes the activation of primordial follicles through mTOR signaling. These findings provide new insight into the relationship between glycolytic disorders and POI/PCOS. CI - (c) 2022. The Author(s). FAU - Zhang, Xiaodan AU - Zhang X AUID- ORCID: 0000-0002-0311-5271 AD - State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, 100193, Beijing, China. AD - Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, 510006, Guangzhou, China. FAU - Zhang, Wenbo AU - Zhang W AD - Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, 510006, Guangzhou, China. FAU - Wang, Zhijuan AU - Wang Z AD - Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, 510006, Guangzhou, China. FAU - Zheng, Nana AU - Zheng N AD - State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, 100193, Beijing, China. AD - Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, 510006, Guangzhou, China. FAU - Yuan, Feifei AU - Yuan F AD - State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, 100193, Beijing, China. AD - Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, 510006, Guangzhou, China. FAU - Li, Biao AU - Li B AD - State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, 100193, Beijing, China. AD - Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, 510006, Guangzhou, China. FAU - Li, Xuelan AU - Li X AD - The Center for Reproductive Medicine, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), 528300, Foshan, Guangdong, China. FAU - Deng, Ling AU - Deng L AD - The Center for Reproductive Medicine, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), 528300, Foshan, Guangdong, China. FAU - Lin, Min AU - Lin M AD - The Center for Reproductive Medicine, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), 528300, Foshan, Guangdong, China. FAU - Chen, Xin AU - Chen X AUID- ORCID: 0000-0001-7407-2929 AD - The Center for Reproductive Medicine, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), 528300, Foshan, Guangdong, China. zhiduoxinrun@hotmail.com. FAU - Zhang, Meijia AU - Zhang M AUID- ORCID: 0000-0001-7803-3054 AD - Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, 510006, Guangzhou, China. zhangmeijia@scut.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220127 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 8558G7RUTR (Pyruvic Acid) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Female MH - Glycolysis MH - *Granulosa Cells/metabolism MH - Mammals MH - Mice MH - Oocytes/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Pyruvic Acid/metabolism MH - *TOR Serine-Threonine Kinases/metabolism PMC - PMC8795455 COIS- The authors declare no competing interests. EDAT- 2022/01/29 06:00 MHDA- 2022/04/09 06:00 PMCR- 2022/01/27 CRDT- 2022/01/28 05:51 PHST- 2021/09/25 00:00 [received] PHST- 2022/01/11 00:00 [accepted] PHST- 2021/12/09 00:00 [revised] PHST- 2022/01/28 05:51 [entrez] PHST- 2022/01/29 06:00 [pubmed] PHST- 2022/04/09 06:00 [medline] PHST- 2022/01/27 00:00 [pmc-release] AID - 10.1038/s41419-022-04541-1 [pii] AID - 4541 [pii] AID - 10.1038/s41419-022-04541-1 [doi] PST - epublish SO - Cell Death Dis. 2022 Jan 27;13(1):87. doi: 10.1038/s41419-022-04541-1.