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, ... More
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.
