Large-scale chemical dissection of mitochondrial function

Abstract

Mitochondrial oxidative phosphorylation (OXPHOS) is central to physiology and disease pathogenesis. To systematically investigate its activity and regulation, we performed a wide range of assays of OXPHOS physiology and nuclear and mitochondrial gene expression across 2490 chemical perturbations in muscle cells. Through mining of the resulting compendium, we discovered that: (1) protein synthesis inhibitors can de-couple coordination of nuclear and mitochondrial transcription; (2) a subset of HMG-CoA reductase inhibitors, in combination with nonselective beta-adrenergic receptor antagonists, can cause mitochondrial toxicity, providing clues into statin-associated myopathy; and (3) structurally diverse microtubule inhibitors stimulate OXPHOS transcription while suppressing reactive oxygen species, via a PGC-1α/ERRα-dependent mechanism, and thus may have utility in treating age-associated degenerative disorders. Our screening compendium is freely available and can be used as a discovery tool for understanding mitochondrial biology and toxicity, and identifying novel therapeutics.