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

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

Author information

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.

PMID:
24945157
PMCID:
PMC4063685
DOI:
10.1371/journal.pgen.1004385
[Indexed for MEDLINE]
Free PMC Article
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