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

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

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.

Original languageEnglish (US)
Article numbere1004385
JournalPLoS genetics
Volume10
Issue number6
DOIs
StatePublished - Jun 2014
Externally publishedYes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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