title: Loss of UCP2 attenuates mitochondrial dysfunction without altering ROS production and uncoupling activity.
abstract: Although mitochondrial dysfunction is often accompanied by excessive reactive oxygen species (ROS) production, we previously showed that an increase in random somatic mtDNA mutations does not result in increased oxidative stress. Normal levels of ROS and oxidative stress could also be a result of an active compensatory mechanism such as a mild increase in proton leak. Uncoupling protein 2 (UCP2) was proposed to play such a role in many physiological situations. However, we show that upregulation of UCP2 in mtDNA mutator mice is not associated with altered proton leak kinetics or ROS production, challenging the current view on the role of UCP2 in energy metabolism. Instead, our results argue that high UCP2 levels allow better utilization of fatty acid oxidation resulting in a beneficial effect on mitochondrial function in heart, postponing systemic lactic acidosis and resulting in longer lifespan in these mice. This study proposes a novel mechanism for an adaptive response to mitochondrial cardiomyopathy that links changes in metabolism to amelioration of respiratory chain deficiency and longer lifespan.
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany; Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kukat
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Sukru Anil
authors.initials: SA
authors.lastname: Dogan
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Edgar
authors.affiliation: Max Planck Institute for Biology of Aging, Cologne, Germany.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Mourier
authors.affiliation: Department of Cardiovascular Physiology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Jacoby
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Maiti
authors.affiliation: Max Planck Institute for Neurological Research, Cologne, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Mauer
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Becker
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Senft
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Wibom
authors.affiliation: Department of Epileptology, University of Bonn, Bonn, Germany.
authors.forename: Alexei P
authors.initials: AP
authors.lastname: Kudin
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.affiliation: Department of Cardiovascular Physiology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Flögel
authors.affiliation: Department III of Internal Medicine, University of Cologne, Cologne, Germany; Cologne Cardiovascular Research Center (CCRC) and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Rosenkranz
authors.affiliation: University Paris Descartes, Faculty of Medicine, CNRS FRE3210, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricquier
authors.affiliation: Department of Epileptology, University of Bonn, Bonn, Germany.
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany; Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Cologne Cardiovascular Research Center (CCRC) and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Trifunovic
mesh_terms: D000140:Acidosis, Lactic / Q000378:metabolism; D000818:Animals; D009202:Cardiomyopathies / Q000473:pathology; D004435:Eating / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics*; D005227:Fatty Acids / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics*; D008017:Life Expectancy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017494:Proton Pumps / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D005227:Fatty Acids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017494:Proton Pumps; D017382:Reactive Oxygen Species; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2