Journal
CELL METABOLISM
Volume 19, Issue 4, Pages 642-652Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2014.01.016
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Funding
- NIH Office of Research Infrastructure Programs [P40 OD010440]
- Mitani lab
- Deutsche Forschungsgemeinschaft
- DIP8 grant [2014376]
- CECAD
- CoEN grant (an initiative of the DZNE)
- CoEN grant (an initiative of CIHR)
- CoEN grant (an initiative of MRC)
- German Federal Ministry of Education and Research (BMBF) [0315088]
- BMBF [0315581]
- [FOR885]
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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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