COX15 deficiency causes oocyte ferroptosis

• 成果类型: Article
• 署名作者: Zhang, Zhihua; Yu, Ran; Shi, Qiuwen; Wu, Zhi-Jing; Li, Qingchun; Mu, Jian; Chen, Biaobang; Shi, Juanzi; Ni, Renmin; Wu, Ling; Li, Qiaoli; Fu, Jing; Li, Rong; Sun, Xiaoxi; Wang, Jiucun; He, Lin; Kuang, Yanping; Sang, Qing; Wang, Lei
• 署名单位: Fudan University; Guangxi Medical University; Chinese Academy of Sciences; Center for Excellence in Molecular Cell Science, CAS; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Binzhou Medical University; Shanghai Academy of Science & Technology; Shanghai Jiao Tong University; Fudan University; Fudan University; Shanghai Jiao Tong University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9491
• DOI: 10.1073/pnas.2406174121
• 发表日期: 2024-11-05
• 关键词: mitochondria; maturation; mutations; genetics; members; FAMILY; heme

摘要

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 Fe2+ 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.