Granulosa cell mevalonate pathway abnormalities contribute to oocyte meiotic defects

The mechanisms of aging-related oocyte meiotic defects and low competence remain elusive. Hi-C and SMART-seq revealed aging-related decreases in chromosome condensation, particularly for genomic regions proximal to the centromeres in metaphase I aged oocytes. Further transcriptomic analysis of oocyte-surrounding granulosa cells (GCs) showed that oocyte meiotic maturation was accompanied by robust increases in mevalonate (MVA) pathway gene expression in GCs, which was largely downregulated in aged GCs. Suppression of MVA metabolism in GCs with statins resulted in marked meiotic defects in young cumulus-oocyte complexes (COCs). Conversely, supplementation with the MVA metabolite geranylgeraniol ameliorated meiotic defects in aged COCs. Meanwhile, geranylgeraniol also activated LHR/EGF signaling in aged GCs and then enhanced the meiosis-associated gene expression in oocytes. Generally, the MVA pathway in GCs is a critical regulator of meiotic maturation in oocytes.