The proteostatic landscape of healthy human oocytes

Oocytes are among the longest-lived cells in the body. Recent studies on mouse oocytes highlight unique adaptations in protein homeostasis (proteostasis) within these cells. However, the mechanisms of proteostasis in human oocytes remain virtually unstudied. We present the first large-scale study of proteostatic activity in human oocytes using over 100 freshly-donated oocytes from 21 healthy women aged 19-34. We analyzed the activity and distribution of lysosomes, proteasomes, and mitochondria in both immature and mature oocytes. In contrast to mice, where degradative activity increases during oocyte maturation, human oocytes exhibit nearly 2-fold lower degradative activity than surrounding somatic cells, which decreases further as oocytes mature. Oocyte maturation is also coupled with a decrease in mitochondrial membrane potential. We propose that reduced organelle activity preserves cellular components during the prolonged maturation in human oocytes. Our findings highlight the need to directly investigate human oocyte biology to address challenges in female fertility.