{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T03:58:50Z","timestamp":1789185530898,"version":"build-2803163510"},"reference-count":69,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T00:00:00Z","timestamp":1738627200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 GM116807"],"award-info":[{"award-number":["R01 GM116807"]}]},{"name":"NIH","award":["R01 NS120322"],"award-info":[{"award-number":["R01 NS120322"]}]},{"name":"NIH","award":["U44 NS125160"],"award-info":[{"award-number":["U44 NS125160"]}]},{"name":"NIH","award":["R01 NS134695"],"award-info":[{"award-number":["R01 NS134695"]}]},{"name":"NIH","award":["HT9425-24-1-0073"],"award-info":[{"award-number":["HT9425-24-1-0073"]}]},{"name":"Office of the Assistant Secretary of Defense for Health Affairs","award":["R01 GM116807"],"award-info":[{"award-number":["R01 GM116807"]}]},{"name":"Office of the Assistant Secretary of Defense for Health Affairs","award":["R01 NS120322"],"award-info":[{"award-number":["R01 NS120322"]}]},{"name":"Office of the Assistant Secretary of Defense for Health Affairs","award":["U44 NS125160"],"award-info":[{"award-number":["U44 NS125160"]}]},{"name":"Office of the Assistant Secretary of Defense for Health Affairs","award":["R01 NS134695"],"award-info":[{"award-number":["R01 NS134695"]}]},{"name":"Office of the Assistant Secretary of Defense for Health Affairs","award":["HT9425-24-1-0073"],"award-info":[{"award-number":["HT9425-24-1-0073"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>It was previously reported that tyrosine 97 (Y97) of cytochrome c is phosphorylated in cow heart tissue under physiological conditions. Y97 phosphorylation was shown to partially inhibit respiration in vitro in the reaction with purified cytochrome c oxidase. Here, we use phosphomimetic Y97E Cytc to further characterize the functional effects of this modification both in vitro and in cell culture models. In vitro, phosphomimetic Y97E Cytc showed lower activity in the reaction with purified cow heart cytochrome c oxidase (COX), decreased caspase-3 activity, and reduced rate of reduction. Additionally, the phosphomimetic Y97E Cytc tended to be resistant to heme degradation and showed an increased rate of oxidation. Intact mouse Cytc double knockout fibroblasts were transfected with plasmids coding for phosphomimetic Y97E Cytc and other variants. Compared to cells expressing wild-type Cytc, the cells expressing phosphomimetic Y97E Cytc showed reduced respiration, mitochondrial membrane potential, and reactive oxygen species production, and protection from apoptosis. In an oxygen\u2013glucose deprivation\/reoxygenation cell culture model of ischemia\/reperfusion injury, mitochondrial membrane potential and reactive oxygen species production were decreased. These data show that Cytc phosphorylation controls the overall flux through the electron transport chain by maintaining optimal intermediate \u0394\u03a8m potentials for efficient ATP production while minimizing reactive oxygen species production, thus protecting the cell from apoptosis.<\/jats:p>","DOI":"10.3390\/ijms26031314","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T05:13:43Z","timestamp":1738646023000},"page":"1314","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Cardiac Tyrosine 97 Phosphorylation of Cytochrome c Regulates Respiration and Apoptosis"],"prefix":"10.3390","volume":"26","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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3477-4659","authenticated-orcid":false,"given":"Vignesh","family":"Pasupathi","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":"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"}]},{"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":[[2025,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s00018-013-1341-1","article-title":"The role of key residues in structure, function, and stability of cytochrome-c","volume":"71","author":"Zaidi","year":"2014","journal-title":"Cell. 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