{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:29:20Z","timestamp":1787005760668,"version":"build-2736575974"},"reference-count":50,"publisher":"National Academy of Sciences","issue":"45","license":[{"start":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T00:00:00Z","timestamp":1730160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82288102 82325021 32130029 82171643 82371662 82001538"],"award-info":[{"award-number":["82288102 82325021 32130029 82171643 82371662 82001538"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The National Natural Key R&D Program of China","award":["2021YFC2700100"],"award-info":[{"award-number":["2021YFC2700100"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,11,5]]},"abstract":"<jats:p>\n                    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\u2013based burden test for mitochondrial genes and identified a candidate gene, cytochrome c oxidase assembly protein 15 (\n                    <jats:italic>COX15).<\/jats:italic>\n                    We report that biallelic\n                    <jats:italic>COX15<\/jats:italic>\n                    pathogenic variants cause human oocyte ferroptosis and female infertility in a recessive inheritance pattern.\n                    <jats:italic>COX15<\/jats:italic>\n                    variants impaired mitochondrial respiration in\n                    <jats:italic>Saccharomyces cerevisiae<\/jats:italic>\n                    and led to reduced protein levels in HeLa cells. Oocyte-specific deletion of\n                    <jats:italic>Cox15<\/jats:italic>\n                    led to impaired Fe\n                    <jats:sup>2+<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2406174121","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T13:36:55Z","timestamp":1730209015000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":28,"title":["<i>COX15<\/i>\n                    deficiency causes oocyte ferroptosis"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4725-883X","authenticated-orcid":false,"given":"Zhihua","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Pediatrics, Children\u2019s Hospital of Fudan University, The Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan 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