PKD regulates mitophagy to prevent oxidative stress and mitochondrial dysfunction during mouse oocyte maturation

Abstract

Mitochondria play dominant roles in various cellular processes such as energy production, apoptosis, calcium homeostasis, and oxidation–reduction balance. Maintaining mitochondrial quality through mitophagy is essential, especially as its impairment leads to the accumulation of dysfunctional mitochondria in aging oocytes. Our previous research revealed that PKD expression decreases in aging oocytes, and its inhibition negatively impacts oocyte quality. Given PKD's role in autophagy mechanisms, this study investigates whether PKD regulates mitophagy to maintain mitochondrial function and support oocyte maturation. When fully grown oocytes were treated with CID755673, a potent PKD inhibitor, we observed meiosis arrest at the metaphase I stage, along with decreased spindle stability. Our results demonstrate an association with mitochondrial dysfunction, including reduced ATP production and fluctuations in Ca2+ homeostasis, which ultimately lead to increased ROS accumulation, stimulating oxidative stress-induced apoptosis and DNA damage. Further research has revealed that these phenomena result from PKD inhibition, which affects the phosphorylation of ULK, thereby reducing autophagy levels. Additionally, PKD inhibition leads to decreased Parkin expression, which directly and negatively affects mitophagy. These defects result in the accumulation of damaged mitochondria in oocytes, which is the primary cause of mitochondrial dysfunction. Taken together, these findings suggest that PKD regulates mitophagy to support mitochondrial function and mouse oocyte maturation, offering insights into potential targets for improving oocyte quality and addressing mitochondrial-related diseases in aging females.