Mitochondrial Regulation of the 26S Proteasome
The more we understand about cell biology, the more we can improve pharmacological treatments. In this study, researchers from several German institutions investigated the link between mitochondrial respiration and proteasomal degradation mechanisms, with important implications for cancer drugs. Applying state-of-the-art molecular biology techniques including phosphoproteomics and metabolomics, these findings demonstrate the role of aspartate and pyruvate at the crossroads of these molecular pathways.
Mitochondrial mutations in respiratory complex I (which can cause malignancies) typically lead to an accumulation of NADH in the mitochondria. This triggers a negative feedback mechanism that inhibits the tricarboxylic acid (TCA) cycle. In turn, this results in a dramatic decrease in the levels of aspartate, a downstream metabolite of the TCA cycle intermediate, oxaloacetate. In this study, researchers linked these lower aspartate levels to an inhibition of 26S proteasome complexes assembly, via the action of aspartate on mTOR complex 1 (mTORC1), which governs the transcription of proteasome assembly factors.
When mitochondrial respiration is impaired, supplementing with aspartate or pyruvate (an electron acceptor) was shown to restore proteasome assembly and activity. The team looked at what this might mean for cancer treatments using bortezomib, a proteasome inhibitor.
Pyruvate supplementation was shown to enable proteasome inhibition by bortezomib in respiration-deficient cells. The team also looked at how the anti-diabetic drug, metformin, might increase bortezomib resistance by inhibiting mitochondrial respiration complex I and impairing 26S proteasome activity. Co-treatment with metformin and pyruvate was found to alleviate this effect and restore bortezomib sensitivity.
Meul T, Berschneider K, Schmitt S, Mayr CH, Mattner LF, Schiller HB, Yazgili AS, Wang X, Lukas C, Schlesser C, Prehn C, Adamski J, Graf E, Schwarzmayr T, Perocchi F, Kukat A, Trifunovic A, Kremer L, Prokisch H, Popper B, von Toerne C, Hauck SM, Zischka H, Meiners S: Mitochondrial Regulation of the 26S Proteasome (2020) Cell Reports | https://doi.org/10.1016/j.celrep.2020.108059