title: Mitochondrial Reactive Oxygen Species Mediate Cardiac Structural, Functional, and Mitochondrial Consequences of Diet-Induced Metabolic Heart Disease.
abstract: BACKGROUND
  Mitochondrial reactive oxygen species (ROS) are associated with metabolic heart disease (MHD). However, the mechanism by which ROS cause MHD is unknown. We tested the hypothesis that mitochondrial ROS are a key mediator of MHD.
  
  
  RESULTS
  Mice fed a high-fat high-sucrose (HFHS) diet develop MHD with cardiac diastolic and mitochondrial dysfunction that is associated with oxidative posttranslational modifications of cardiac mitochondrial proteins. Transgenic mice that express catalase in mitochondria and wild-type mice were fed an HFHS or control diet for 4 months. Cardiac mitochondria from HFHS-fed wild-type mice had a 3-fold greater rate of H2O2 production (P=0.001 versus control diet fed), a 30% decrease in complex II substrate-driven oxygen consumption (P=0.006), 21% to 23% decreases in complex I and II substrate-driven ATP synthesis (P=0.01), and a 62% decrease in complex II activity (P=0.002). In transgenic mice that express catalase in mitochondria, all HFHS diet-induced mitochondrial abnormalities were ameliorated, as were left ventricular hypertrophy and diastolic dysfunction. In HFHS-fed wild-type mice complex II substrate-driven ATP synthesis and activity were restored ex vivo by dithiothreitol (5 mmol/L), suggesting a role for reversible cysteine oxidative posttranslational modifications. In vitro site-directed mutation of complex II subunit B Cys100 or Cys103 to redox-insensitive serines prevented complex II dysfunction induced by ROS or high glucose/high palmitate in the medium.
  
  
  CONCLUSIONS
  Mitochondrial ROS are pathogenic in MHD and contribute to mitochondrial dysfunction, at least in part, by causing oxidative posttranslational modifications of complex I and II proteins including reversible oxidative posttranslational modifications of complex II subunit B Cys100 and Cys103.
authors.affiliation: Myocardial Biology Unit, Boston University School of Medicine, Boston, MA (A.L.S., A.E., F.Q., I.L., T.D.C., D.A.S., E.J.M., D.R.P., W.S.C.).
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sverdlov
authors.affiliation: Myocardial Biology Unit, Boston University School of Medicine, Boston, MA (A.L.S., A.E., F.Q., I.L., T.D.C., D.A.S., E.J.M., D.R.P., W.S.C.).
authors.forename: Aly
authors.initials: A
authors.lastname: Elezaby
authors.affiliation: Myocardial Biology Unit, Boston University School of Medicine, Boston, MA (A.L.S., A.E., F.Q., I.L., T.D.C., D.A.S., E.J.M., D.R.P., W.S.C.).
authors.forename: Fuzhong
authors.initials: F
authors.lastname: Qin
authors.affiliation: Vascular Biology Section, Boston University School of Medicine, Boston, MA (J.B.B., R.A.C., M.M.B.).
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Behring
authors.affiliation: Myocardial Biology Unit, Boston University School of Medicine, Boston, MA (A.L.S., A.E., F.Q., I.L., T.D.C., D.A.S., E.J.M., D.R.P., W.S.C.).
authors.forename: Ivan
authors.initials: I
authors.lastname: Luptak
authors.affiliation: Myocardial Biology Unit, Boston University School of Medicine, Boston, MA (A.L.S., A.E., F.Q., I.L., T.D.C., D.A.S., E.J.M., D.R.P., W.S.C.).
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Calamaras
authors.affiliation: Myocardial Biology Unit, Boston University School of Medicine, Boston, MA (A.L.S., A.E., F.Q., I.L., T.D.C., D.A.S., E.J.M., D.R.P., W.S.C.).
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Siwik
authors.affiliation: Myocardial Biology Unit, Boston University School of Medicine, Boston, MA (A.L.S., A.E., F.Q., I.L., T.D.C., D.A.S., E.J.M., D.R.P., W.S.C.).
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Miller
authors.affiliation: Obesity and Nutrition Section, Mitochondria ARC, Boston University School of Medicine, Boston, MA (M.L., O.S.S.).
authors.forename: Marc
authors.initials: M
authors.lastname: Liesa
authors.affiliation: Obesity and Nutrition Section, Mitochondria ARC, Boston University School of Medicine, Boston, MA (M.L., O.S.S.).
authors.forename: Orian S
authors.initials: OS
authors.lastname: Shirihai
authors.affiliation: Myocardial Biology Unit, Boston University School of Medicine, Boston, MA (A.L.S., A.E., F.Q., I.L., T.D.C., D.A.S., E.J.M., D.R.P., W.S.C.).
authors.forename: David R
authors.initials: DR
authors.lastname: Pimentel
authors.affiliation: Vascular Biology Section, Boston University School of Medicine, Boston, MA (J.B.B., R.A.C., M.M.B.).
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cohen
authors.affiliation: Vascular Biology Section, Boston University School of Medicine, Boston, MA (J.B.B., R.A.C., M.M.B.).
authors.forename: Markus M
authors.initials: MM
authors.lastname: Bachschmid
authors.affiliation: Myocardial Biology Unit, Boston University School of Medicine, Boston, MA (A.L.S., A.E., F.Q., I.L., T.D.C., D.A.S., E.J.M., D.R.P., W.S.C.).
authors.forename: Wilson S
authors.initials: WS
authors.lastname: Colucci
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D019422:Dietary Sucrose; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D009154:Mutation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D016277:Ventricular Function, Left
chemical_list: D019422:Dietary Sucrose; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D002374:Catalase; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I
keywords: metabolic heart disease; mitochondria; obesity; oxidative protein modifications; oxidative stress