Mitochondrial unfoldase ClpX regulates oocyte competence during ovarian aging

Abstract Ovarian aging has reproductive and overall health implications with increased infertility, miscarriage rates, and adverse outcomes associated with menopause. Mitochondrial dysfunction is one of the key factors in reproductive aging. However, the role of mitochondrial proteostasis in determining oocyte quality is underexplored. In this manuscript, we report that mitochondrial protein unfoldase ClpX (Caseinolytic Protease X) is essential to maintain oocyte quality with aging. ClpX deficiency, either through genetic ablation or natural decline with aging in mice, led to the disrupted mitochondrial proteostasis in oocytes. Oocyte-specific knockout of Clpx impaired oocyte quality and developmental competence, thereby leading to female subfertility. Oocyte transcriptomic and nano-proteomic analyses demonstrated altered mitochondrial function and protein processing. Notably, Clpx deficiency promoted PGD2 synthesis by upregulating Ptgds . The PGD2 synthesis inhibitor AT-56 restored the developmental competence of Clpx knockout and aged mouse oocytes. Translationally, AT-56 administration improved human oocyte in vitro maturation. This study highlights the role of mitochondrial proteostasis in determining oocyte quality with aging and underscores its importance as a potential therapeutic target for infertility.