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In this study, we investigated the effect of Y48 modification in a double-knockout cell culture model that stably expressed either unphosphorylated wild-type (WT) Cytc, control Y48F Cytc, or phosphomimetic Y48E Cytc. Our findings revealed that Y48E Cytc caused partial inhibition of mitochondrial respiration in intact cells, which corresponded with lower mitochondrial membrane potentials (\u0394\u03a8m) and reduced reactive oxygen species (ROS) production. When subjected to an oxygen\u2013glucose deprivation\/reoxygenation (OGD\/R) model, which simulates ischemia\/reperfusion injury, the Y48E phosphomimetic cell line showed lower ROS production compared to the unphosphorylated WT and Y48F Cytc cell lines, the latter of which generated higher levels of ROS upon reoxygenation. As a result, the Y48E Cytc cell line had significantly lower cell death rates when exposed to OGD\/R, confirming the cytoprotective role of Y48 phosphorylation of Cytc. In summary, our research indicates that the loss of Y48 phosphorylation in Cytc during ischemia leads to reperfusion injury by driving maximum electron transport chain flow, hyperpolarization of \u0394\u03a8m, bursts of ROS, and death of cells through apoptosis.<\/jats:p>","DOI":"10.3390\/biom16050632","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T11:40:12Z","timestamp":1777981212000},"page":"632","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Tyrosine 48 Phosphorylation of Cytochrome c Alters Mitochondrial Respiration, ROS Production, and Apoptosis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1530-1466","authenticated-orcid":false,"given":"Paul T.","family":"Morse","sequence":"first","affiliation":[{"name":"Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Vuljaj","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA"},{"name":"Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabil","family":"Yazdi","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew P.","family":"Zurek","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5867-0694","authenticated-orcid":false,"given":"Junmei","family":"Wan","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Icksoo","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Medicine, Dankook University, Cheonan-si 31116, Chungcheongnam-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmita","family":"Vaishnav","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1571-2866","authenticated-orcid":false,"given":"Brian F.P.","family":"Edwards","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9644-3494","authenticated-orcid":false,"given":"Tasnim","family":"Arroum","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6310-7081","authenticated-orcid":false,"given":"Maik","family":"H\u00fcttemann","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA"},{"name":"Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4166","DOI":"10.1038\/s41467-023-39820-8","article-title":"Cytochrome c lysine acetylation regulates cellular respiration and cell death in ischemic skeletal muscle","volume":"14","author":"Morse","year":"2023","journal-title":"Nat. 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