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...

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Published in:Cell metabolism Vol. 19; no. 4; p. 642
Main Authors: Segref, Alexandra, Kevei, Éva, Pokrzywa, Wojciech, Schmeisser, Kathrin, Mansfeld, Johannes, Livnat-Levanon, Nurit, Ensenauer, Regina, Glickman, Michael H, Ristow, Michael, Hoppe, Thorsten
Format: Journal Article
Language:English
Published: United States 01.04.2014
Subjects:
Adenosine Triphosphate - metabolism
Animals
Animals, Genetically Modified
Caenorhabditis elegans
Cell Line
Cyclooxygenase 1 - genetics
Electrophoresis, Polyacrylamide Gel
Green Fluorescent Proteins
Humans
Immunoblotting
Mitochondrial Diseases - metabolism
Mitochondrial Diseases - physiopathology
Mutagenesis
Organic Chemicals
Oxidative Phosphorylation
Proteasome Endopeptidase Complex - metabolism
Proteolysis
Reactive Oxygen Species - metabolism
Ubiquitin - metabolism
Ubiquitin-Protein Ligases - metabolism
ISSN:1932-7420, 1932-7420
Online Access:Get more information
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Summary: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.
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ISSN:1932-7420
1932-7420
DOI:10.1016/j.cmet.2014.01.016