title: Electron flow into cytochrome c coupled with reactive oxygen species from the electron transport chain converts cytochrome c to a cardiolipin peroxidase: role during ischemia-reperfusion.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Hema S
authors.initials: HS
authors.lastname: Aluri
authors.affiliation: Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Simpson
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Allegood
authors.affiliation: Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Karol
authors.initials: K
authors.lastname: Szczepanek
authors.affiliation: Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Gronert
authors.affiliation: Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lesnefsky
keywords: Cardiolipin; Cytochrome c peroxidase; Ischemia–reperfusion; Methionine sulfoxide; Mitochondria; ROS
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