title: Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure.
abstract: Mitochondrial reactive oxygen species (ROS) play a central role in most aging-related diseases. ROS are produced at the respiratory chain that demands NADH for electron transport and are eliminated by enzymes that require NADPH. The nicotinamide nucleotide transhydrogenase (Nnt) is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Here, we show that pathological metabolic demand reverses the direction of the Nnt, consuming NADPH to support NADH and ATP production, but at the cost of NADPH-linked antioxidative capacity. In heart, reverse-mode Nnt is the dominant source for ROS during pressure overload. Due to a mutation of the Nnt gene, the inbred mouse strain C57BL/6J is protected from oxidative stress, heart failure, and death, making its use in cardiovascular research problematic. Targeting Nnt-mediated ROS with the tetrapeptide SS-31 rescued mortality in pressure overload-induced heart failure and could therefore have therapeutic potential in patients with this syndrome.
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Nickel
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: von Hardenberg
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Hohl
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany.
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Löffler
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kohlhaas
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany.
authors.forename: Janne
authors.initials: J
authors.lastname: Becker
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany.
authors.forename: Jan-Christian
authors.initials: JC
authors.lastname: Reil
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany.
authors.forename: Andrey
authors.initials: A
authors.lastname: Kazakov
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bonnekoh
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Stadelmaier
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany.
authors.forename: Sarah-Lena
authors.initials: SL
authors.lastname: Puhl
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Department of Biophysics, CIPMM, School of Medicine, Saarland University, 66421 Homburg, Germany.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bogeski
authors.affiliation: Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Cortassa
authors.affiliation: Department of Biophysics, CIPMM, School of Medicine, Saarland University, 66421 Homburg, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kappl
authors.affiliation: Department of Biophysics, CIPMM, School of Medicine, Saarland University, 66421 Homburg, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Pasieka
authors.affiliation: Department of Structural Biology, Saarland University, 66421 Homburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lafontaine
authors.affiliation: Department of Structural Biology, Saarland University, 66421 Homburg, Germany.
authors.forename: C Roy D
authors.initials: CR
authors.lastname: Lancaster
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK; Department of Physics and Astronomy, University College London, London WC1E 6BT, UK.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Blacker
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London WC1E 6BT, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hall
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Duchen
authors.affiliation: Institut für Zellbiologie, Universität des Saarlandes, 66421 Homburg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kästner
authors.affiliation: Institut für Zellbiologie, Universität des Saarlandes, 66421 Homburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lipp
authors.affiliation: Klinik für Allgemeine und Interventionelle Kardiologie, Universitäres Herzzentrum Hamburg, 20246 Hamburg, Germany; Deutsches Zentrum für Herzkreislaufforschung (DZHK e.V.), Partner Site Hamburg/Lübeck/Kiel, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Zeller
authors.affiliation: Klinik für Allgemeine und Interventionelle Kardiologie, Universitäres Herzzentrum Hamburg, 20246 Hamburg, Germany; Deutsches Zentrum für Herzkreislaufforschung (DZHK e.V.), Partner Site Hamburg/Lübeck/Kiel, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Müller
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Knopp
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Laufs
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.affiliation: Department of Biophysics, CIPMM, School of Medicine, Saarland University, 66421 Homburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hoth
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany. Electronic address: christoph.maack@uks.eu.
authors.forename: Christoph
authors.initials: C
authors.lastname: Maack
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D005978:Glutathione / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D009249:NADP / Q000378:metabolism*; D009250:NADP Transhydrogenases / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D009249:NADP; D000255:Adenosine Triphosphate; D009250:NADP Transhydrogenases; D005978:Glutathione