Autophagy dictates PHGDH-mediated serine metabolism in a timely manner to support oocyte development

The metabolic co-dependence of the oocyte and surrounding granulosa cells is crucial for oocyte developmental competence. Previous research has shown that serine-glycine and its key downstream metabolites are significantly involved in the process of oocyte maturation. However, the mechanism of serine metabolism and its influence on oocyte maturation remain unclear. In this study, we demonstrate that the serine metabolism enzyme PHGDH, which mediates de novo serine synthesis, is highly activated in granulosa cells and plays a crucial role in maintaining their metabolic and transcriptional homeostasis. By using our previously reported granulosa cell-oocyte co-culture system, we found that macroautophagy/autophagy regulates oocyte maturation by modulating PHGDH-mediated serine metabolism in a stage-specific manner, and this regulation is mediated by CALCOCO2/NDP52-dependent selective autophagy. Additional experiments indicated that S-adenosylmethionine (SAM) is a potential downstream product of serine metabolism, and that restoring SAM significantly rescues both granulosa cell homeostasis and oocyte quality. At the molecular level, we demonstrated that SAM regulates Igf1 expression by altering the H3K4me3 modification level in its promoter region, highlighting a serine-SAM-H3K4me3-Igf1 regulatory axis during oocyte maturation. Finally, we demonstrated that oocyte developmental capacity depends on de novo serine synthesis in granulosa cells during germinal vesicle breakdown (GVBD) stage rather than on the exogenous uptake of serine, and that disruption of serine synthesis significantly affects oocyte developmental capacity. Overall, our findings reveal how serine metabolism links granulosa cells and oocytes, provides new targets for predicting oocyte quality, and may help with strategies for early diagnosis or therapeutic intervention in improving reproductive outcomes.Abbreviations aa: amino acid; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; COCs: cumulus-oocyte complexes; CQ: chloroquine; DEG: differentially expressed gene; GV: germinal vesicle; GVBD: germinal vesicle breakdown; IGF1: insulin-like growth factor 1; MII: metaphase II stage of meiosis; OPTN: optineurin; Pb1: first polar body: PHGDH: 3-phosphoglycerate dehydrogenase; ROS: reactive oxygen species; SAM: s-adenosylmethionine; SQSTM1/p62: sequestosome 1; Ub: ubiquitin; WT: wild-type.