Mitochondrial Regulation of the 26S Proteasome

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. © 2020 The Author(s)Meul et al. demonstrate reversible regulation of 26S proteasome assembly and activity by metabolic reprogramming of the TCA cycle upon impaired respiratory function. Supplementation with aspartate or pyruvate restores 26S proteasome activity via mTORC1-mediated transcriptional activation of defined proteasome assembly factors. © 2020 The Author(s)