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Despite these extensive past studies, its molecular function has yet to be discovered. Here, we applied an interdisciplinary approach and discovered an explicit nitric oxide (NO) access site to the mitoNEET [2Fe\u20102S] cluster. We found that O<jats:sub>2<\/jats:sub> and pioglitazone block NO access to the cluster, suggesting a molecular function for the mitoNEET [2Fe\u20102S] cluster in mitochondrial signal transduction. Our discovery hints at a new pathway <jats:italic>via<\/jats:italic> which mitochondria can sense hypoxia through O<jats:sub>2<\/jats:sub> protection of the mitoNEET [2Fe\u20102S] cluster, a new paradigm in understanding the importance of [Fe\u2010S] clusters for gasotransmitter signal transduction in eukaryotes.<\/jats:p>","DOI":"10.1002\/1873-3468.15097","type":"journal-article","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T05:54:12Z","timestamp":1736142852000},"page":"952-970","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The [<scp>2Fe<\/scp>\u2010<scp>2S<\/scp>] cluster of mitochondrial outer membrane protein <scp>mitoNEET<\/scp> has an <scp>O<sub>2<\/sub><\/scp>\u2010regulated nitric oxide access tunnel"],"prefix":"10.1002","volume":"599","author":[{"given":"Thao Nghi","family":"Hoang","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Science King's College London  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