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

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

Research output: Contribution to journalArticle

51 Citations (Scopus)

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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Mitochondrial Diseases
Proteasome Endopeptidase Complex
Ubiquitin
Reactive Oxygen Species
Mitochondria
Mitochondrial Proteins
Caenorhabditis elegans
Proteolysis
Oxidation-Reduction
Disease Progression
Respiration
Homeostasis
Adenosine Triphosphate
Apoptosis
Mutation
Therapeutics

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology
  • Medicine(all)

Cite this

Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system. / Segref, Alexandra; Kévei, E.; Pokrzywa, Wojciech; Schmeisser, Kathrin; Mansfeld, Johannes; Livnat-Levanon, Nurit; Ensenauer, Regina; Glickman, Michael H.; Ristow, Michael; Hoppe, Thorsten.

In: Cell Metabolism, Vol. 19, No. 4, 01.04.2014, p. 642-652.

Research output: Contribution to journalArticle

Segref, A, Kévei, E, Pokrzywa, W, Schmeisser, K, Mansfeld, J, Livnat-Levanon, N, Ensenauer, R, Glickman, MH, Ristow, M & Hoppe, T 2014, 'Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system', Cell Metabolism, vol. 19, no. 4, pp. 642-652. https://doi.org/10.1016/j.cmet.2014.01.016
Segref, Alexandra ; Kévei, E. ; Pokrzywa, Wojciech ; Schmeisser, Kathrin ; Mansfeld, Johannes ; Livnat-Levanon, Nurit ; Ensenauer, Regina ; Glickman, Michael H. ; Ristow, Michael ; Hoppe, Thorsten. / Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system. In: Cell Metabolism. 2014 ; Vol. 19, No. 4. pp. 642-652.
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