Meul, Thomas, Berschneider, Korbinian, Schmitt, Sabine, Mayr, Christoph H., Mattner, Laura F., Schiller, Herbert B., Yazgili, Ayse S., Wang, Xinyuan, Lukas, Christina, Schlesser, Camille, Prehn, Cornelia ORCID: 0000-0002-1274-4715, Adamski, Jerzy, Graf, Elisabeth, Schwarzmayr, Thomas, Perocchi, Fabiana, Kukat, Alexandra, Trifunovic, Aleksandra, Kremer, Laura, Prokisch, Holger, Popper, Bastian, von Toerne, Christine, Hauck, Stefanie M., Zischka, Hans and Meiners, Silke (2020). Mitochondria! Regulation of the 26S Proteasome. Cell Reports, 32 (8). CAMBRIDGE: CELL PRESS. ISSN 2211-1247

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Abstract

The proteasome is the main proteolytic system for targeted protein degradation in the cell and is fine-tuned according to cellular needs. Here, we demonstrate that mitochondrial dysfunction and concomitant metabolic reprogramming of the tricarboxylic acid (TCA) cycle reduce the assembly and activity of the 26S proteasome. Both mitochondrial mutations in respiratory complex I and treatment with the anti-diabetic drug metformin impair 26S proteasome activity. Defective 26S assembly is reversible and can be overcome by supplementation of aspartate or pyruvate. This metabolic regulation of 26S activity involves specific regulation of proteasome assembly factors via the mTORC1 pathway. Of note, reducing 26S activity by metformin confers increased resistance toward the proteasome inhibitor bortezomib, which is reversible upon pyruvate supplementation. Our study uncovers unexpected consequences of defective mitochondrial metabolism for proteasomal protein degradation in the cell, which has important pathophysiological and therapeutic implications.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Meul, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berschneider, KorbinianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mayr, Christoph H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mattner, Laura F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schiller, Herbert B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yazgili, Ayse S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, XinyuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lukas, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlesser, CamilleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prehn, CorneliaUNSPECIFIEDorcid.org/0000-0002-1274-4715UNSPECIFIED
Adamski, JerzyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Graf, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwarzmayr, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perocchi, FabianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kukat, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trifunovic, AleksandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kremer, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prokisch, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Popper, BastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Toerne, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hauck, Stefanie M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zischka, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meiners, SilkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-322690
DOI: 10.1016/j.celrep.2020.108059
Journal or Publication Title: Cell Reports
Volume: 32
Number: 8
Date: 2020
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 2211-1247
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
COMPLEX I DEFICIENCY; PROTEIN-SYNTHESIS; MUTATIONS CAUSE; CULTURED-CELLS; DEGRADATION; PHOSPHORYLATION; DISEASES; SUBUNITS; PATHWAY; SYSTEMMultiple languages
Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/32269

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