Loss of UCP2 Attenuates Mitochondrial Dysfunction without Altering ROS Production and Uncoupling Activity

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

doi:10.1371/journal.pgen.1004385

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.

Highlights

Mitochondria are organelles found in almost every eukaryotic cell
Depletion of Uncoupling protein 2 (UCP2) in mtDNA mutator mice led to further shortening of the lifespan with earlier signs of mitochondrial cardiomyopathy accompanied with high systemic lactic acidosis, often used as a marker of mitochondrial diseases
Our results demonstrate that the presence of UCP2 wields beneficial effect on respiratory deficient mitochondria without affecting reactive oxygen species (ROS) production or uncoupling

Summary

Introduction

Mitochondria are organelles found in almost every eukaryotic cell They produce the bulk of cellular energy in the form of ATP, which is required for numerous processes in the cell. The mitochondrial theory of aging proposes that an age-driven accumulation of mtDNA mutations will compromise electron transport leading to an increase in ROS production [1]. We challenged this theory by showing that increased levels of random mtDNA mutations lead to the development of premature aging phenotypes in mtDNA mutator mice, without affecting ROS production or increasing oxidative stress [2,3]. A mild uncoupling of oxidative phosphorylation, leading to decreased mitochondrial ATP production could be sufficient to reduce ROS generation in the cell [4]. Uncoupling proteins (UCPs) are proposed to have a central role in this process (for review see [5])

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