| 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 |
21.567
|
| Times Cited |
60
|
|
WOS Category
|
ENDOCRINOLOGY & METABOLISM
CELL BIOLOGY
|
| Resource |
| C.elegans |
tm2371
tm544
tm4853 |
