Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system

Cell Metab. 2014 Apr 1;19(4):642-52. doi: 10.1016/j.cmet.2014.01.016.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • MitoTracker Red 580
  • Organic Chemicals
  • Reactive Oxygen Species
  • Ubiquitin
  • Green Fluorescent Proteins
  • Adenosine Triphosphate
  • Cyclooxygenase 1
  • PTGS1 protein, human
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex