Loss of UCP2 attenuates mitochondrial dysfunction without altering ROS production and uncoupling activity

Alexandra Kukat; Sukru Anil Dogan; Daniel Edgar; Arnaud Mourier; Christoph Jacoby; Priyanka Maiti; Jan Mauer; Christina Becker; Katharina Senft; Rolf Wibom; Alexei P Kudin; Kjell Hultenby; Ulrich Flögel; Stephan Rosenkranz; Daniel Ricquier; Wolfram S Kunz; Aleksandra Trifunovic

doi:10.1371/journal.pgen.1004385

Loss of UCP2 attenuates mitochondrial dysfunction without altering ROS production and uncoupling activity

PLoS Genet. 2014 Jun 19;10(6):e1004385. doi: 10.1371/journal.pgen.1004385. eCollection 2014 Jun.

Authors

Alexandra Kukat¹, Sukru Anil Dogan², Daniel Edgar³, Arnaud Mourier⁴, Christoph Jacoby⁵, Priyanka Maiti², Jan Mauer⁶, Christina Becker², Katharina Senft², Rolf Wibom³, Alexei P Kudin⁷, Kjell Hultenby³, Ulrich Flögel⁵, Stephan Rosenkranz⁸, Daniel Ricquier⁹, Wolfram S Kunz⁷, Aleksandra Trifunovic¹⁰

Affiliations

¹ 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.
² 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.
³ Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
⁴ Max Planck Institute for Biology of Aging, Cologne, Germany.
⁵ Department of Cardiovascular Physiology, Heinrich-Heine-University, Düsseldorf, Germany.
⁶ Max Planck Institute for Neurological Research, Cologne, Germany.
⁷ Department of Epileptology, University of Bonn, Bonn, Germany.
⁸ 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.
⁹ University Paris Descartes, Faculty of Medicine, CNRS FRE3210, Paris, France.
¹⁰ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acidosis, Lactic / metabolism
Animals
Cardiomyopathies / pathology
Eating / genetics
Energy Metabolism / genetics*
Fatty Acids / metabolism*
Ion Channels / genetics*
Life Expectancy
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria, Heart / genetics
Mitochondria, Heart / metabolism*
Mitochondrial Diseases / genetics*
Mitochondrial Diseases / metabolism
Mitochondrial Proteins / genetics*
Myocardium / metabolism
Oxidation-Reduction
Oxidative Stress
Proton Pumps / genetics
Reactive Oxygen Species / metabolism
Uncoupling Protein 2

Substances

Fatty Acids
Ion Channels
Mitochondrial Proteins
Proton Pumps
Reactive Oxygen Species
Ucp2 protein, mouse
Uncoupling Protein 2

Grants and funding

AT is supported by grants from The Swedish Research Council, The Åke Wiberg Foundation, CECAD Cologne, The German Research Council, and The European Research Council (ERC contract 310700). SAD and PM are supported by PhD scholarships from CECAD Graduate School. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.