Universität zu Köln

Segref, Alexandra, Kevei, Eva ORCID: 0000-0002-0560-9208, Pokrzywa, Wojciech ORCID: 0000-0002-5110-4462, Schmeisser, Kathrin, Mansfeld, Johannes, Livnat-Levanon, Nurit, Ensenauer, Regina, Glickman, Michael H., Ristow, Michael ORCID: 0000-0003-2109-2453 and Hoppe, Thorsten ORCID: 0000-0002-4734-9352 (2014). Pathogenesis of Human Mitochondrial Diseases Is Modulated by Reduced Activity of the Ubiquitin/Proteasome System. Cell Metab., 19 (4). S. 642 - 653. CAMBRIDGE: CELL PRESS. ISSN 1932-7420

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Segref, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Kevei, Eva UNSPECIFIED orcid.org/0000-0002-0560-9208 UNSPECIFIED Pokrzywa, Wojciech UNSPECIFIED orcid.org/0000-0002-5110-4462 UNSPECIFIED Schmeisser, Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Mansfeld, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Livnat-Levanon, Nurit UNSPECIFIED UNSPECIFIED UNSPECIFIED Ensenauer, Regina UNSPECIFIED UNSPECIFIED UNSPECIFIED Glickman, Michael H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ristow, Michael UNSPECIFIED orcid.org/0000-0003-2109-2453 UNSPECIFIED Hoppe, Thorsten UNSPECIFIED orcid.org/0000-0002-4734-9352 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-441649
DOI:	10.1016/j.cmet.2014.01.016
Journal or Publication Title:	Cell Metab.
Volume:	19
Number:	4
Page Range:	S. 642 - 653
Date:	2014
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1932-7420
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language UBIQUITIN-PROTEASOME SYSTEM; UNFOLDED PROTEIN RESPONSE; OXIDATIVE-STRESS-RESPONSE; CYTOCHROME-C-OXIDASE; CAENORHABDITIS-ELEGANS; LIFE-SPAN; DEPENDENT PROTEOLYSIS; ISOVALERIC ACIDEMIA; OUTER-MEMBRANE; DEGRADATION Multiple languages Cell Biology; Endocrinology & Metabolism Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/44164