TY - JOUR
T1 - Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system
AU - Segref, Alexandra
AU - Kevei, Éva
AU - Pokrzywa, Wojciech
AU - Schmeisser, Kathrin
AU - Mansfeld, Johannes
AU - Livnat-Levanon, Nurit
AU - Ensenauer, Regina
AU - Glickman, Michael H.
AU - Ristow, Michael
AU - Hoppe, Thorsten
N1 - Funding Information: We thank S. Greco-Torres, G. Vopper, and S. Wullinger for technical support; M. Doitsidou, O. Hobert, and S. Motameny for advice on next generation sequencing analysis; A. Eck for advice on ATP measurements; and T. Wenz for comments on the manuscript. C. elegans strains were kindly provided by the Caenorhabditis Genetics Center (funded by the NIH Office of Research Infrastructure Programs, P40 OD010440) and the Mitani lab. We thank A. Fire, H. Kashkar, R. Wiesner, the Dana-Farber Cancer Institute, and Geneservice Ltd. for antibodies, plasmids, cDNAs, and patient cell lines. We particularly thank M.H.G. for exchange of unpublished results. This work is supported by grants of the Deutsche Forschungsgemeinschaft, especially the DIP8 grant 2014376 to M.H.G. and T.H., and CECAD and FOR885 to T.H.; by the CoEN grant (an initiative of the DZNE, CIHR, and MRC) to T.H.; by the German Federal Ministry of Education and Research (BMBF) grant 0315088 to R.E.; and by BMBF grant 0315581 for Systems Biology of Ageing (JenAge) to M.R.
PY - 2014/4/1
Y1 - 2014/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84897528338&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2014.01.016
DO - 10.1016/j.cmet.2014.01.016
M3 - مقالة
SN - 1550-4131
VL - 19
SP - 642
EP - 652
JO - Cell Metabolism
JF - Cell Metabolism
IS - 4
ER -