Mitochondrial Regulation of the 26S Proteasome

Thomas Meul, Korbinian Berschneider, Sabine Schmitt, Christoph H. Mayr, Laura F. Mattner, Herbert B. Schiller, Ayse S. Yazgili, Xinyuan Wang, Christina Lukas, Camille Schlesser, Cornelia Prehn, Jerzy Adamski, Elisabeth Graf, Thomas Schwarzmayr, Fabiana Perocchi, Alexandra Kukat, Aleksandra Trifunovic, Laura Kremer, Holger Prokisch, Bastian PopperChristine von Toerne, Stefanie M. Hauck, Hans Zischka, Silke Meiners

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish
Article number108059
JournalCell Reports
Volume32
Issue number8
DOIs
StatePublished - 25 Aug 2020
Externally publishedYes

Keywords

  • 26S proteasome
  • Rpn6
  • TCA
  • aspartate
  • metabolic reprogramming
  • metformin
  • mitochondria
  • proteasome assembly factors
  • proteasome inhibitor resistance
  • pyruvate
  • respiratory complex I

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