Hema S Aluri1, David C Simpson2, Jeremy C Allegood3, Ying Hu4, Karol Szczepanek4, Scott Gronert2, Qun Chen4, Edward J Lesnefsky5. 1. Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA 23298, USA. 2. Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284, USA. 3. Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA. 4. Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA. 5. Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA 23298, USA; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA; Cardiology Section Medical Service, McGuire Veterans Affairs Medical Center, Richmond, VA 23249, USA. Electronic address: edward.lesnefsky@va.gov.
Abstract
BACKGROUND: Cytochrome c (Cyt c) is a mobile component of the electron transport chain (ETC.) which contains a tightly coordinated heme iron. In pathologic settings, a key ligand of the cyt c's heme iron, methionine (Met80), is oxidized allowing cyt c to participate in reactions as a peroxidase with cardiolipin as a target. Myocardial ischemia (ISC) results in ETC. blockade and increased production of reactive oxygen species (ROS). We hypothesized that during ischemia-reperfusion (ISC-REP); ROS generation coupled with electron flow into cyt c would oxidize Met80 and contribute to mitochondrial-mediated ETC. damage. METHODS: Mitochondria were incubated with specific substrates and inhibitors to test the contributions of ROS and electron flow into cyt c. Subsequently, cyt c and cardiolipin were analyzed. To test the pathophysiologic relevance, mouse hearts that underwent ISC-REP were tested for methionine oxidation in cyt c. RESULTS: The combination of substrate/inhibitor showed that ROS production and electron flux through cyt c are essential for the oxidation of methionine residues that lead to cardiolipin depletion. The content of cyt c methionine oxidation increases following ISC-REP in the intact heart. CONCLUSIONS: Increase in intra-mitochondrial ROS coupled with electron flow into cyt c, oxidizes cyt c followed by depletion of cardiolipin. ISC-REP increases methionine oxidation, supporting that cyt c peroxidase activity can form in the intact heart. GENERAL SIGNIFICANCE: This study identifies a new site in the ETC. that is damaged during cardiac ISC-REP. Generation of a neoperoxidase activity of cyt c favors the formation of a defective ETC. that activates signaling for cell death. Published by Elsevier B.V.
BACKGROUND: Cytochrome c (Cyt c) is a mobile component of the electron transport chain (ETC.) which contains a tightly coordinated hemeiron. In pathologic settings, a key ligand of the cyt c's hemeiron, methionine (Met80), is oxidized allowing cyt c to participate in reactions as a peroxidase with cardiolipin as a target. Myocardial ischemia (ISC) results in ETC. blockade and increased production of reactive oxygen species (ROS). We hypothesized that during ischemia-reperfusion (ISC-REP); ROS generation coupled with electron flow into cyt c would oxidize Met80 and contribute to mitochondrial-mediated ETC. damage. METHODS: Mitochondria were incubated with specific substrates and inhibitors to test the contributions of ROS and electron flow into cyt c. Subsequently, cyt c and cardiolipin were analyzed. To test the pathophysiologic relevance, mouse hearts that underwent ISC-REP were tested for methionine oxidation in cyt c. RESULTS: The combination of substrate/inhibitor showed that ROS production and electron flux through cyt c are essential for the oxidation of methionine residues that lead to cardiolipin depletion. The content of cyt cmethionine oxidation increases following ISC-REP in the intact heart. CONCLUSIONS: Increase in intra-mitochondrial ROS coupled with electron flow into cyt c, oxidizes cyt c followed by depletion of cardiolipin. ISC-REP increases methionine oxidation, supporting that cyt c peroxidase activity can form in the intact heart. GENERAL SIGNIFICANCE: This study identifies a new site in the ETC. that is damaged during cardiac ISC-REP. Generation of a neoperoxidase activity of cyt c favors the formation of a defective ETC. that activates signaling for cell death. Published by Elsevier B.V.
Entities:
Keywords:
Cardiolipin; Cytochrome c peroxidase; Ischemia–reperfusion; Methionine sulfoxide; Mitochondria; ROS
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