O-059 ntermetabolites of cholesterol synthesis in granulosa cell and oocyte aging

Abstract With the development of society, there has been a significant delay in female fertility and an increasing desire for childbearing among females of advanced maternal age in recent decades. Nevertheless, women over 35 years old have more risk of infertility and miscarriage compared to young women, due to decreased oocyte quality. These changes are mainly caused by meiotic defects, especially aneuploidy. Therefore, exploring the mechanisms of aging-related meiotic defects and aneuploidy in oocytes is of great significant for improving the pregnancy outcomes of aged women. Oocytes are enveloped by granulosa cells (GCs) to form follicles, which constitute the reproductive units in ovaries. GCs form a metabolic community with oocytes for oocyte growth and maturation. Numerous studies have reported that metabolic coupling between GCs and oocytes could affect the process of oocyte meiosis resumption, spindle assembly, and chromatin arrangement. Maternal aging is related to disruption of oocyte-GC interactions that leads to disorders of the oocyte meiotic process. Therefore, abnormal metabolic coupling between GCs and oocytes is an important reason for decreased quality in aged oocytes. To further clarify the metabolic coupling changes between GCs and oocytes during ovarian aging, we systematically characterized the dynamic changes in the overall transcriptomic landscapes of oocytes and GCs from young and aged mice throughout oocyte meiosis (during the growing oocyte [GO], full-grown oocyte [FGO], metaphase I [MI] oocyte [MIO], and metaphase II [MII] oocyte [MIIO] phases). Data revealed that the mevalonate (MVA) pathway, an essential metabolic pathway that uses acetyl-CoA to produce cholesterol and isoprenoids, was specifically highly expressed in GCs with the resumption of oocyte meiosis, and the expression of MVA pathway in GCs decreased with age. Atorvastatin-mediated inhibition of MVA metabolism in GCs decreased the first polar body extrusion (PBE) rate, and increased oocyte meiotic defects and aneuploidy in young cumulus-oocyte complexes (COCs). Further studies showed that the effect of the MVA pathway on oocyte meiosis was mainly regulated by protein isoprenoylation mediated by the inter-metabolites of cholesterol synthesis. Importantly, upregulation of the MVA pathway in aged GCs could ameliorate the depletion of ovarian reserve, decrease oocyte meiotic defects, and improve oocyte quality. In conclusion, metabolite in granulosa cell is an important factor determining the oocyte quality; MVA pathway in GCs is a critical regulator of meiotic maturation and euploidy in oocytes, and age-associated MVA pathway abnormalities contribute to oocyte meiotic defects and aneuploidy; Supplementation of inter-metabolites of cholesterol synthesis is a new therapeutic target for clinical intervention to improve oocyte quality. Trial registration number XXXX