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Mitochondrial Regulation of the 26S Proteasome. 2020
Thomas Meul, and
Korbinian Berschneider, and
Sabine Schmitt, and
Christoph H Mayr, and
Laura F Mattner, and
Herbert B Schiller, and
Ayse S Yazgili, and
Xinyuan Wang, and
Christina Lukas, and
Camille Schlesser, and
Cornelia Prehn, and
Jerzy Adamski, and
Elisabeth Graf, and
Thomas Schwarzmayr, and
Fabiana Perocchi, and
Alexandra Kukat, and
Aleksandra Trifunovic, and
Laura Kremer, and
Holger Prokisch, and
Bastian Popper, and
Christine von Toerne, and
Stefanie M Hauck, and
Hans Zischka, and
Silke Meiners
Member of the German Center for Lung Research (DZL), Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, 81377 Munich, Germany.
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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