Aggregation of Respiratory Complex Subunits Marks the Onset of Proteotoxicity in Proteasome Inhibited Cells |
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| Affiliation: | 1. Center for Integrated Protein Science at the Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85748 Garching, Germany;2. Institute of Structural Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany;3. Gottfried Schatz Research Center, Medical University of Graz, 8036 Graz, Austria;4. BioTechMed-Graz, 8010 Graz, Austria;3. Program in Computational Biology and Bioinformatics, Center for Biologically Inspired Materials and Material Systems, Duke University, Durham, North Carolina 27705;4. Department of Chemistry, and Center for Biologically Inspired Materials and Material Systems, Duke University, Durham, North Carolina 27705;5. Department of Mechanical Engineering and Materials Science, Center for Biologically Inspired Materials and Material Systems, Duke University, Durham, North Carolina 27705;1. Department of Biology, Stanford University, Stanford, CA 94305-5430, USA;2. Department of Biology, University of Konstanz, 78457 Konstanz, Germany;3. Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK;1. Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany;2. Laboratory of Biology Bio@SNS, Scuola Normale Superiore, Pisa, Italy;1. Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany;2. Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany;3. Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691 Stockholm, Sweden;4. Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany;5. Max F. Perutz Laboratories, Vienna Biocenter, University of Vienna, 1030 Vienna, Austria;6. III. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany;7. Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany;8. BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany;9. CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany;10. Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria;3. Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands;4. Center for Molecular Biology of the University of Heidelberg and the German Cancer Research Center, 69120 Heidelberg, Germany;5. Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia |
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| Abstract: | Proteostasis is maintained by optimal expression, folding, transport, and clearance of proteins. Deregulation of any of these processes triggers protein aggregation and is implicated in many age-related pathologies. In this study, using quantitative proteomics and microscopy, we show that aggregation of many nuclear-encoded mitochondrial proteins is an early protein destabilization event during short-term proteasome inhibition. Among these, respiratory chain complex (RCC) subunits represent a group of functionally related proteins consistently forming aggregates under multiple proteostasis stresses with varying aggregation propensities. Sequence analysis reveals that several RCC subunits, irrespective of the cleavable mitochondrial targeting sequence, contain low-complexity regions at the N-terminus. Using different chimeric and mutant constructs, we show that these low-complexity regions partially contribute to the intrinsic instability of multiple RCC subunits. Taken together, we propose that physicochemically driven aggregation of unassembled RCC subunits destabilizes their functional assembly inside mitochondria. This eventually deregulates the biogenesis of respiratory complexes and marks the onset of mitochondrial dysfunction. |
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