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Meul, T. ; Berschneider, K. ; Schmitt, S. ; Mayr, C. ; Mattner, L. ; Schiller, H. B. ; Yazgili, A.S. ; Wang, X.* ; Lukas, C. ; Schlesser, C. ; Prehn, C. ; Adamski, J. ; Graf, E. ; Schwarzmayr, T. ; Perocchi, F. ; Kukat, A.* ; Trifunovic, A.* ; Kremer, L.S. ; Prokisch, H. ; Popper, B.* ; von Toerne, C. ; Hauck, S.M. ; Zischka, H. ; Meiners, S.

Mitochondrial regulation of the 26S proteasome.

Cell Rep. 32:108059 (2020)
Publ. Version/Full Text Research data DOI
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords 26s Proteasome ; Aspartate ; Metabolic Reprogramming ; Metformin ; Mitochondria ; Proteasome Assembly Factors ; Proteasome Inhibitor Resistance ; Pyruvate ; Respiratory Complex I ; Rpn6 ; Tca; Complex I Deficiency; Protein-synthesis; Mutations Cause; Cultured-cells; Degradation; Phosphorylation; Diseases; Subunits; Pathway; System
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Journal Cell Reports
Quellenangaben Volume: 32, Issue: 8, Pages: , Article Number: 108059 Supplement: ,
Publisher Cell Press
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Lung Health and Immunity (LHI)
Institute of Molecular Toxicology and Pharmacology (TOXI)
Molekulare Endokrinologie und Metabolismus (MEM)
Institute of Human Genetics (IHG)
Institute of Diabetes and Obesity (IDO)
Institute of Neurogenomics (ING)
CF Metabolomics & Proteomics (CF-MPC)