Decreased PTGES2 Farnesylation in Granulosa Cells Compromises PGE2‐Dependent Cumulus Expansion and Oocyte Maturation During Ovarian Aging

TL;DR

This study shows that reduced farnesylation of PTGES2 in aging granulosa cells impairs oocyte maturation and cumulus expansion, offering a potential treatment to improve fertility in older women.

Contribution

The study identifies PTGES2 farnesylation as a novel mechanism linking ovarian aging to oocyte quality decline.

Findings

Aged granulosa cells show reduced protein farnesylation, impairing cumulus expansion and oocyte maturation.

Farnesol supplementation restores farnesylation and improves oocyte quality in aged mice.

PTGES2 farnesylation is essential for its ER localization and PGE2 production in granulosa cells.

Abstract

With the increasing trend of delayed childbearing, the decline in oocyte quality associated with advanced maternal age has emerged as a pressing concern. However, the mechanism remains unclear, and effective strategies for improvement are currently lacking. Previously, we reported that the downregulation of the mevalonate pathway in aged granulosa cells (GCs) contributed to meiotic defects in oocytes, which may implicate farnesyl pyrophosphate‐mediated protein farnesylation. Nevertheless, the role of farnesylation in ovarian aging and its impact on oocytes requires further investigation. In this study, using cumulus‐oocyte complexes (COCs) from young and aged female mice, we observed impaired cumulus expansion and concurrent meiotic defects during aged oocyte maturation, accompanied by significantly reduced protein farnesylation in aged GCs. Furthermore, inhibiting farnesylation with FTI‐277 in young COCs recapitulated the aging phenotype, disrupting cumulus expansion and inducing meiotic defects similar to those in aged COCs. Conversely, restoring farnesylation via farnesol supplementation effectively ameliorated these deficits in both aged COCs (in vitro) and aged mice (in vivo). Proteomic analysis and experimental validation identified prostaglandin E2 synthase 2 (PTGES2) as a farnesylated protein. Mechanistically, age‐related decline in PTGES2 farnesylation in GCs reduces its endoplasmic reticulum localization and impairs prostaglandin E2 (PGE2) production, thereby compromising PGE2‐dependent cumulus expansion and oocyte maturation. Collectively, our findings highlight the detrimental effects of decreased farnesylation in aged GCs on oocyte quality and propose a potential therapeutic strategy for improving the developmental competence of aged oocytes.

A schematic showing decreased PTGES2 farnesylation in granulosa cells compromises PGE2‐dependent cumulus expansion and oocyte maturation during ovarian aging. In young ovaries, PTGES2 farnesylation of GCs regulates the process of cumulus expansion and oocyte maturation by facilitating PGE2 production. With aging, the downregulation of PTGES2 farnesylation in GCs disrupts PTGES2 localization to the ER, thereby impairing cumulus expansion and oocyte maturation through reduced PGE2 production.

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