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Cell Metab. 2014 Apr 1;19(4):642-52. doi: 10.1016/j.cmet.2014.01.016.

Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system.

Author information

1
Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Strasse 47a, 50674 Cologne, Germany.
2
Department of Human Nutrition, Institute of Nutrition, University of Jena, 07743 Jena, Germany.
3
Department of Human Nutrition, Institute of Nutrition, University of Jena, 07743 Jena, Germany; Energy Metabolism Laboratory, ETH Zürich, Schwerzenbach/Zürich, CH 8603, Switzerland.
4
Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
5
Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, 80337 Munich, Germany.
6
Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Strasse 47a, 50674 Cologne, Germany. Electronic address: thorsten.hoppe@uni-koeln.de.

Abstract

Mitochondria maintain cellular homeostasis by coordinating ATP synthesis with metabolic activity, redox signaling, and apoptosis. Excessive levels of mitochondria-derived reactive oxygen species (ROS) promote mitochondrial dysfunction, triggering numerous metabolic disorders. However, the molecular basis for the harmful effects of excessive ROS formation is largely unknown. Here, we identify a link between mitochondrial stress and ubiquitin-dependent proteolysis, which supports cellular surveillance both in Caenorhabditis elegans and humans. Worms defective in respiration with elevated ROS levels are limited in turnover of a GFP-based substrate protein, demonstrating that mitochondrial stress affects the ubiquitin/proteasome system (UPS). Intriguingly, we observed similar proteolytic defects for disease-causing IVD and COX1 mutations associated with mitochondrial failure in humans. Together, these results identify a conserved link between mitochondrial metabolism and ubiquitin-dependent proteostasis. Reduced UPS activity during pathological conditions might potentiate disease progression and thus provides a valuable target for therapeutic intervention.

PMID:
24703696
DOI:
10.1016/j.cmet.2014.01.016
[Indexed for MEDLINE]
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