Selective autophagic degradation of ACLY (ATP citrate lyase) maintains citrate homeostasis and promotes oocyte maturation

自噬 ATP柠檬酸裂解酶 卵母细胞 生物 细胞生物学 柠檬酸合酶 卵泡发生 卵泡液 内分泌学 生物化学 细胞凋亡 胚胎 低温保存
作者
Hainan He,Junling Wang,Xingmei Mou,Xin Liu,Qiao Li,Mingyue Zhong,Bingbing Luo,Zhisheng Yu,Jingjing Zhang,Tian Xu,Chengli Dou,Dan‐Ya Wu,Wei Qing,Linhui Wu,Zongke Zhou,Zhengang Fan,Tingting Wang,Taotao Hu,Xia Zhang,Jilong Zhou,Yi‐Liang Miao
出处
期刊:Autophagy [Informa]
卷期号:19 (1): 163-179 被引量:18
标识
DOI:10.1080/15548627.2022.2063005
摘要

ABSTRACTMacroautophagy/autophagy is a cellular and energy homeostatic mechanism that contributes to maintain the number of primordial follicles, germ cell survival, and anti-ovarian aging. However, it remains unknown whether autophagy in granulosa cells affects oocyte maturation. Here, we show a clear tendency of reduced autophagy level in human granulosa cells from women of advanced maternal age, implying a potential negative correlation between autophagy levels and oocyte quality. We therefore established a co-culture system and show that either pharmacological inhibition or genetic ablation of autophagy in granulosa cells negatively affect oocyte quality and fertilization ability. Moreover, our metabolomics analysis indicates that the adverse impact of autophagy impairment on oocyte quality is mediated by downregulated citrate levels, while exogenous supplementation of citrate can significantly restore the oocyte maturation. Mechanistically, we found that ACLY (ATP citrate lyase), which is a crucial enzyme catalyzing the cleavage of citrate, was preferentially associated with K63-linked ubiquitin chains and recognized by the autophagy receptor protein SQSTM1/p62 for selective autophagic degradation. In human follicles, the autophagy level in granulosa cells was downregulated with maternal aging, accompanied by decreased citrate in the follicular fluid, implying a potential correlation between citrate metabolism and oocyte quality. We also show that elevated citrate levels in porcine follicular fluid promote oocyte maturation. Collectively, our data reveal that autophagy in granulosa cells is a beneficial mechanism to maintain a certain degree of citrate by selectively targeting ACLY during oocyte maturation.Abbreviations: 3-MA: 3-methyladenine; ACLY: ATP citrate lyase; AMA: advanced maternal age; CG: cortical granule; CHX: cycloheximide; CQ: chloroquine; CS: citrate synthase; COCs: cumulus-oocyte-complexes; GCM: granulosa cell monolayer; GV: germinal vesicle; MII: metaphase II stage of meiosis; PB1: first polar body; ROS: reactive oxygen species; shRNA: small hairpin RNA; SQSTM1/p62: sequestosome 1; TCA: tricarboxylic acid; TOMM20/TOM20: translocase of outer mitochondrial membrane 20; UBA: ubiquitin-associated domain; Ub: ubiquitin; WT: wild-typeKEYWORDS: ACLYcitrateoocyte maturationselective autophagySQSTM1/p62 AcknowledgmentsWe thank Dr. Heide Schatten (University of Missouri) for helping us to improve our English language. We are grateful to Fangke Wang for her assistance in the pattern diagram drawing.Data availabilityAll sequencing data related to this study have been deposited at Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/) under the accession number GSE190697.Disclosure statementNo potential conflict of interest was reported by the author(s).Supplementary materialSupplemental data for this article can be accessed here.Additional informationFundingThis work was supported by the National Natural Science Foundation of China (Grant# 31801242), Key Research and Development Program of Hubei Province (Grant# 2021BBA221), the project supported by the Fundamental Research Funds for the Central University (Grant# 2662020DKQD001), Hubei Province Science and Technology Basic Conditions Platform (2020DFE020).
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