NEDDylation modifies mitochondrial transcription to maintain oocyte quality (Oocyte)

Aging decreases oocyte quality, leading to infertility, miscarriage, and birth defects. Major contributors to this decline include mitochondrial dysfunction and chromosome dynamics dysregulation. Here, we show that oocyte-specific deletion of Uba3, which encodes the catalytic subunit of the E1 NEDDylation activating complex (NAE), in mice causes sterility and premature depletion of the ovarian reserve. Fully grown Uba3 conditional knockout oocytes show hallmarks of mitochondrial abnormalities, including increased reactive oxygen species, decreased oxidative phosphorylation, and increased unhealthy mitochondria. These discoveries provide insight into mechanisms governing oocyte quality and a regulatory role of NEDDylation for mitochondrial transcription in gametes. Overall design: We performed RNA-sequencing analysis on 3 control and 3 Uba3 cKO pools of ~150 GV oocytes per pool