COX15 deficiency causes oocyte ferroptosis

作者：Zhihua Zhang, Ran Yu, Qiuwen Shi, Zhi-Jing Wu, Qingchun Li, Qingchun Li, Jian Mu, Biaobang Chen, Juanzi Shi, Renmin Ni, Ling Wu, Qiaoli Li, Rong Li, Jing Fu, Rong Li, Xiaoxi Sun, Jiucun Wang, Lin He, Yanping Kuang, Qing Sang, Lei Wang · 发表于：Proceedings of the National Academy of Sciences · 年份：2024 · DOI：10.1073/pnas.2406174121 · 被引用次数：26 · 研究领域：Epigenetics and DNA Methylation、Ferroptosis and cancer prognosis、RNA modifications and cancer

Mitochondria play diverse roles in mammalian physiology. The architecture, activity, and physiological functions of mitochondria in oocytes are largely different from those in somatic cells, but the mitochondrial proteins related to oocyte quality and reproductive longevity remain largely unknown. Here, using whole-exome sequencing data from 1,024 women (characterized by oocyte maturation arrest and degenerated or morphologically abnormal oocytes) and 2,868 healthy controls, we performed a population and gene–based burden test for mitochondrial genes and identified a candidate gene, cytochrome c oxidase assembly protein 15 ( COX15). We report that biallelic COX15 pathogenic variants cause human oocyte ferroptosis and female infertility in a recessive inheritance pattern. COX15 variants impaired mitochondrial respiration in Saccharomyces cerevisiae and led to reduced protein levels in HeLa cells. Oocyte-specific deletion of Cox15 led to impaired Fe 2+ and reactive oxygen species homeostasis that caused mitochondrial dysfunction and ultimately sensitized oocytes to ferroptosis. In addition, ferrostatin-1 (an inhibitor of ferroptosis) could rescue the oocyte ferroptosis phenotype in vitro and ex vivo. Our findings not only provide a genetic diagnostic marker for oocyte development defects but also expand the spectrum of mitochondrial disorders to female infertility and contribute to unique insights into the role of ferroptosis in human oocyte defects.