A functional neddylation pathway underlies oocyte quality and aging

点击翻译按钮获取中文摘要

ABSTRACT Women have a short reproductive window compared to their overall lifespan. Fertility usually peaks around age 25, but a subsequent loss of oocyte quality and oocyte numbers leads to reproductive decline followed by menopause around age 51. This becomes a health concern as women increasingly delay childbearing until they are past ‘advanced maternal age’ (AMA) (i.e., ages 35+). AMA women are at risk of increased aneuploidy that leads to miscarriage, birth defects, premature birth and other high-risk pregnancies. This is primarily driven by defects in oocyte quality, as women undergoing artificial reproductive technologies using young donor eggs have similar pregnancy rates at all ages. While poorly defined, declines in oocyte quality can be attributed to several factors, including defective chromosome structure, proteostasis, and mitochondria, but much of why oocyte quality is lost overtime is unknown. We recently generated a novel oocyte-specific conditional knockout (ocKO) for a central enzyme (UBA3) required for the post-translational modification (PTM), neddylation. Neddylation covalently attaches the small ubiquitin-like protein, NEDD8, to target proteins via an E1-E2-E3 enzymatic cascade to regulate protein structure, function, stability, and subcellular localization. The role of neddylation in female fertility and oocyte development during folliculogenesis is not known. Our preliminary data show that Uba3 ocKO female mice are sterile, show depletion of most oocytes by young adulthood, and have oocytes with changes in chromosome structure, meiotic resumption, and mitochondrial activity, suggestive of a loss in oocyte quality. As neddylation regulates mitochondrial structure and function in some cells, and mitochondrial function is thought to be a key driver of oocyte quality, our central hypothesis is that neddylation is required for the development of oocytes during folliculogensis in part by regulating mitochondrial function. The Aims of this project are designed to (1) determine how loss of neddylation alters mitochondrial function in oocytes and (2) demonstrate that neddylation activity declines with oocyte aging. The results from these Aims will show for the first time that neddylation is linked to mitochondrial dysfunction in oocytes and that changes in neddylation efficiency may drive aspects of oocyte aging. In addition, these studies will form the foundation of future studies to determine whether neddylation could be exploited in the ART setting as a means to increase oocyte quality in eggs of older women.