Adaptive mitochondrial regulation of the proteasome

Abstract

The proteasome is the main proteolytic system for targeted protein degradation in the cell. Its function is fine-tuned according to cellular needs. Regulation of proteasome function by mitochondrial metabolism, however, is unknown.Here, we demonstrate that mitochondrial dysfunction reduces the assembly and activity of the 26S proteasome in the absence of oxidative stress. Impaired respiratory complex I function leads to metabolic reprogramming of the Krebs cycle and deficiency in aspartate. Aspartate supplementation activates assembly and activity of 26S proteasomes via transcriptional activation of the proteasome assembly factors p28 and Rpn6. This metabolic adaptation of 26S proteasome function involves sensing of aspartate via the mTORC1 pathway. Metformin treatment of primary human cells similarly reduced assembly and activity of 26S proteasome complexes, which was fully reversible and rescued by supplementation of aspartate or pyruvate. Of note, respiratory dysfunction conferred resistance towards the proteasome inhibitor Bortezomib.Our study uncovers a fundamental novel mechanism of how mitochondrial metabolism adaptively adjusts protein degradation by the proteasome. It thus unravels unexpected consequences of defective mitochondrial metabolism in disease or drug-targeted mitochondrial reprogramming for proteasomal protein degradation in the cell. As metabolic inhibition of proteasome function can be alleviated by treatment with aspartate or pyruvate, our results also have therapeutic implications. 4 Keywords 26S proteasome, mitochondria, respiratory complex I, aspartate, metabolic reprogramming, proteasome assembly factors, pyruvate 5

Reprograming of proteasomal degradation by branched chain amino acid metabolism

“…UPS activity is adapted to cellular needs by modulating proteasome quantity and composition (Rousseau & Bertolotti, 2018). Accordingly, reversible proteasome disassembly is triggered by oxidative stress (Grune et al, 2011;Livnat-Levanon et al, 2014;Wang et al, 2010) or metabolic disturbances (Meul et al, 2020). Although metabolic defects and proteostasis decline are linked to numerous pathologies and known hallmarks of aging (Lopez-Otin et al, 2013), the two topics have been mainly examined independently (Ottens et al, 2021).…”