Long live the oocyte: studying protein lifespan in oocyte health

ongoing

Oocytes form during embryonic development and persist in a dormant state for decades, representing some of the longest-lived cells in our body. As oocytes transfer their cytoplasm to the early embryo and the next generation, the regulation of its quality serves as a unique evolutionary strategy to preserve cellular longevity and fertility. Protein turnover is essential for replacing damaged molecules with their functional copies since long lifespans expose proteins to damage accumulation, including age-related post-translational modifications (PTMs). Recent data show that oocytes have low protein turnover rates, suggesting they retain many extremely long-lived proteins (ELLPs). How these ELLPs are stabilized and contribute to oocyte health remains unknown. With this innovative action, I aim to map ELLPs that emerge during oocyte formation and persist throughout its lifetime, characterize the molecular mechanisms by which they are regulated, and functionally assess their role in preserving oocyte quality. I will combine longitudinal labeling-based mass spectrometry with fluorescent imaging to characterize and quantify oocytes’ ELL proteomes and study their regulation by measuring PTMs. I will then combine an oocyte in vitro differentiation protocol with a genetic perturbation screen to investigate ELLP function by selectively and timely perturbing them, determining whether their long-live nature is essential for oocyte quality. Female infertility is one of the biggest societal challenges of our time. Over one in four fertility problems are unexplained, highlighting a significant knowledge gap in female reproduction. This project will provide new insights into the mechanisms by which mammalian oocytes regulate protein homeostasis. Its relevance transcends reproductive biology, filling a critical gap in our understanding of protein quality control mechanisms in non-dividing cells and providing new angles to interpret age-related deterioration and female infertility.