Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system.
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.
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.
Alexandra
A
Segref
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.
Éva
É
Kevei
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.
Wojciech
W
Pokrzywa
Department of Human Nutrition, Institute of Nutrition, University of Jena, 07743 Jena, Germany.
Kathrin
K
Schmeisser
Department of Human Nutrition, Institute of Nutrition, University of Jena, 07743 Jena, Germany; Energy Metabolism Laboratory, ETH Zürich, Schwerzenbach/Zürich, CH 8603, Switzerland.
Johannes
J
Mansfeld
Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
Nurit
N
Livnat-Levanon
Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, 80337 Munich, Germany.
Regina
R
Ensenauer
Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
Michael H
MH
Glickman
Department of Human Nutrition, Institute of Nutrition, University of Jena, 07743 Jena, Germany; Energy Metabolism Laboratory, ETH Zürich, Schwerzenbach/Zürich, CH 8603, Switzerland.
Michael
M
Ristow
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.
Thorsten
T
Hoppe
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D002460:Cell Line; D051545:Cyclooxygenase 1 / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D049452:Green Fluorescent Proteins; D006801:Humans; D015151:Immunoblotting; D028361:Mitochondrial Diseases / Q000378:metabolism* / Q000503:physiopathology; D016296:Mutagenesis; D009930:Organic Chemicals; D010085:Oxidative Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
C507919:MitoTracker Red 580; D009930:Organic Chemicals; D017382:Reactive Oxygen Species; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex