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This study explored the regulatory role of H2S on iron metabolism and mitochondrial functions in cultured rat cardiac cells. Rotenone, a mitochondrial complex I inhibitor, was used for establishing an in vitro model of ischemic cell damage. It was first found that rotenone induced oxidative stress and lipid peroxidation and decreased mitochondrial membrane potential and ATP generation, eventually causing cell death. The supplement of H2S at a physiologically relevant concentration protected from rotenone-induced ferroptotic cell death by reducing oxidative stress and mitochondrial damage, maintaining GPx4 expression and intracellular iron level. Deferiprone, an iron chelator, would also protect from rotenone-induced ferroptosis. Further studies demonstrated that H2S inhibited ABCB8-mediated iron efflux from mitochondria to cytosol and promoted NFS1-mediated Fe-S cluster biogenesis. It is also found that rotenone stimulated iron-dependent H2S generation. These results indicate that H2S would protect cardiac cells from ischemic damage through preserving mitochondrial functions and intracellular Fe-S cluster homeostasis.<\/jats:p>","DOI":"10.3390\/cells13050371","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T04:23:10Z","timestamp":1708489390000},"page":"371","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["H2S Protects from Rotenone-Induced Ferroptosis by Stabilizing Fe-S Clusters in Rat Cardiac Cells"],"prefix":"10.3390","volume":"13","author":[{"given":"Sara","family":"Linjacki","sequence":"first","affiliation":[{"name":"School of Natural Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada"},{"name":"Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, ON P3E 2C6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuehong","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Natural Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada"},{"name":"Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, ON P3E 2C6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navjeet","family":"Baath","sequence":"additional","affiliation":[{"name":"School of Natural Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada"},{"name":"Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, ON P3E 2C6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devin","family":"Mantle","sequence":"additional","affiliation":[{"name":"School of Natural Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada"},{"name":"Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, ON P3E 2C6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3575-7786","authenticated-orcid":false,"given":"Guangdong","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Natural Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada"},{"name":"Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, ON P3E 2C6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1126\/science.1162667","article-title":"H2S as a physiologic vasorelaxant: Hypertension in mice with deletion of cystathionine gamma-lyase","volume":"322","author":"Yang","year":"2008","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.bcp.2017.11.014","article-title":"A review of hydrogen sulfide (H2S) donors: Chemistry and potential therapeutic applications","volume":"149","author":"Powell","year":"2018","journal-title":"Biochem. 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