Mevalonate metabolites boost aged oocyte quality through small GTPases prenylation

Declined oocyte quality is the major contributor to female subfertility in aged mammals. Currently, there are no effective interventions to ameliorate aged oocyte quality. We found that oocytes from aged mice exhibited lower levels of mevalonate (MVA) pathway metabolites, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) and reduced cortical F-actin. We further demonstrated that MVA supplementation improved the FPP level, the cortical F-actin and the quality of aged oocytes. Mechanistically, we found that MVA supplementation induced granulosa cells to synthesize FPP, which was subsequently transferred to aged oocytes. Transported FPP increased small GTPases prenylation, including CDC42 and RAC1, and promoted membrane localization of CDC42-N-WASP-Arp2/3 and RAC1-WAVE2-Arp2/3 complexes, promoting cortical F-actin re-assembly and reducing aneuploidy of aged oocytes. We also identified an oral drug 8-isopentenyl flavone, as an isoprenoid donor from Epimedium brevicornu Maxim, which could increase CDC42 and RAC1 prenylation, improving the cortical F-actin and the competence of aged oocytes, ameliorating reproductive outcomes in aged female mice. Collectively, increasing small GTPases prenylation via MVA metabolites or 8-IPF provide a therapeutic approach for boosting fertility in women of advanced maternal age.