Serine‐47 phosphorylation of cytochrome c in the mammalian brain regulates cytochrome c oxidase and caspase‐3 activity

Kalpage, Hasini A.; Vaishnav, Asmita; Liu, Jenney; Varughese, Ashwathy; Wan, Junmei; Turner, Alice A.; Ji, Qinqin; Zurek, Matthew P.; Kapralov, Alexandr A.; Kagan, Valerian E.; Brunzelle, Joseph S.; Recanati, Maurice‐Andre; Grossman, Lawrence I.; Sanderson, Thomas H.; Lee, Icksoo; Salomon, Arthur R.; Edwards, Brian F. P.; Hüttemann, Maik

doi:10.1096/fj.201901120R

Title: Serine‐47 phosphorylation of cytochrome c in the mammalian brain regulates cytochrome c oxidase and caspase‐3 activity

Journal Article · Sat Sep 28 00:00:00 EDT 2019 · FASEB Journal

DOI:https://doi.org/10.1096/fj.201901120R· OSTI ID:1786938

Kalpage, Hasini A. ^[1]; Vaishnav, Asmita ^[2]; Liu, Jenney ^[1]; Varughese, Ashwathy ^[3]; Wan, Junmei ^[3]; Turner, Alice A. ^[3]; Ji, Qinqin ^[4]; Zurek, Matthew P. ^[1]; Kapralov, Alexandr A. ^[5]; Kagan, Valerian E. ^[6]; Brunzelle, Joseph S. ^[7]; Recanati, Maurice‐Andre ^[8]; Grossman, Lawrence I. ^[1]; Sanderson, Thomas H. ^[9]; Lee, Icksoo ^[10]; Salomon, Arthur R. ^[4]; Edwards, Brian F. P. ^[2]; Hüttemann, Maik ^[11]

Center for Molecular Medicine and Genetics Wayne State University Detroit Michigan USA
Department of Biochemistry, Microbiology, and Immunology Wayne State University Detroit Michigan USA
Center for Molecular Medicine and Genetics Wayne State University Detroit Michigan USA, Department of Biochemistry, Microbiology, and Immunology Wayne State University Detroit Michigan USA
Department of Chemistry Brown University Providence Rhode Island USA
Department of Environmental and Occupational Health Center for Free Radical and Antioxidant Health University of Pittsburgh Pittsburgh Pennsylvania USA
Department of Environmental and Occupational Health Center for Free Radical and Antioxidant Health University of Pittsburgh Pittsburgh Pennsylvania USA, Laboratory of Navigational Redox Lipidomics I. M. Sechenov Moscow Medical State University Moscow Russia
Center for Synchrotron Research Northwestern University Argonne Illinois USA
Center for Molecular Medicine and Genetics Wayne State University Detroit Michigan USA, Department of Obstetrics and Gynecology Wayne State University Detroit Michigan USA
Department of Emergency Medicine University of Michigan Medical School Ann Arbor Michigan USA, Department of Molecular and Integrative Physiology University of Michigan Medical School Ann Arbor Michigan USA, Cardiovascular Research Institute Wayne State University School of Medicine Detroit Michigan USA
College of Medicine, Dankook University Cheonan‐si South Korea
Center for Molecular Medicine and Genetics Wayne State University Detroit Michigan USA, Department of Biochemistry, Microbiology, and Immunology Wayne State University Detroit Michigan USA, Cardiovascular Research Institute Wayne State University School of Medicine Detroit Michigan USA

Cytochrome c (Cyt c ) is a multifunctional protein that operates as an electron carrier in the mitochondrial electron transport chain and plays a key role in apoptosis. We have previously shown that tissue‐specific phosphorylations of Cyt c in the heart, liver, and kidney play an important role in the regulation of cellular respiration and cell death. Here, we report that Cyt c purified from mammalian brain is phosphorylated on S47 and that this phosphorylation is lost during ischemia. We have characterized the functional effects in vitro using phosphorylated Cyt c purified from pig brain tissue and a recombinant phosphomimetic mutant (S47E). We crystallized S47E phosphomimetic Cyt c at 1.55 Å and suggest that it spatially matches S47‐phosphorylated Cyt c , making it a good model system. Both S47‐phosphorylated and phosphomimetic Cyt c showed a lower oxygen consumption rate in reaction with isolated Cyt c oxidase, which we propose maintains intermediate mitochondrial membrane potentials under physiologic conditions, thus minimizing production of reactive oxygen species. S47‐phosphorylated and phosphomimetic Cyt c showed lower caspase‐3 activity. Furthermore, phosphomimetic Cyt c had decreased cardiolipin peroxidase activity and is more stable in the presence of H ₂ O ₂ . Our data suggest that S47 phosphorylation of Cyt c is tissue protective and promotes cell survival in the brain.—Kalpage, H. A., Vaishnav, A., Liu, J., Varughese, A., Wan, J., Turner, A. A., Ji, Q., Zurek, M. P., Kapralov, A. A., Kagan, V. E., Brunzelle, J. S., Recanati, M.‐A., Grossman, L. I., Sanderson, T. H., Lee, I., Salomon, A. R., Edwards, B. F. P, Hüttemann, M. Serine‐47 phosphorylation of cytochrome c in the mammalian brain regulates cytochrome c oxidase and caspase‐3 activity. FASEB J. 33, 13503‐13514 (2019). www.fasebj.org

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Sponsoring Organization:: USDOE

OSTI ID:: 1786938

Journal Information:: FASEB Journal, Journal Name: FASEB Journal Vol. 33 Journal Issue: 12; ISSN 0892-6638

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Country of Publication:: United States

Language:: English

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Cited by: 18 works

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References (54)

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