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

Alexandra Segref, Éva Kevei, Wojciech Pokrzywa, Kathrin Schmeisser, Johannes Mansfeld, Nurit Livnat-Levanon, Regina Ensenauer, Michael H. Glickman, Michael Ristow, Thorsten Hoppe

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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.

Original languageEnglish
Pages (from-to)642-652
Number of pages11
JournalCell Metabolism
Volume19
Issue number4
DOIs
Publication statusPublished - Apr 1 2014

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ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Segref, A., Kevei, É., Pokrzywa, W., Schmeisser, K., Mansfeld, J., Livnat-Levanon, N., Ensenauer, R., Glickman, M. H., Ristow, M., & Hoppe, T. (2014). Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system. Cell Metabolism, 19(4), 642-652. https://doi.org/10.1016/j.cmet.2014.01.016