RRC ID 45852
Author Segref A, Kevei É, Pokrzywa W, Schmeisser K, Mansfeld J, Livnat-Levanon N, Ensenauer R, Glickman MH, Ristow M, Hoppe T.
Title Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system.
Journal Cell Metab.
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.
Volume 19(4)
Pages 642-52
Published 2014-4-1
DOI 10.1016/j.cmet.2014.01.016
PII S1550-4131(14)00022-9
PMID 24703696
MeSH 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
IF 22.415
Times Cited 34
C.elegans tm2371 tm544 tm4853