fg-4592 and antimycin

Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction.

Topics: Anaerobiosis; Animals; Antimycin A; Bacterial Proteins; Biomarkers; Body Temperature; Body Weight; CRISPR-Associated Protein 9; Disease Models, Animal; Electron Transport; Electron Transport Complex I; Endonucleases; Energy Metabolism; Gene Knockout Techniques; Genome-Wide Association Study; Glycine; Humans; Hypoxia-Inducible Factor 1; Isoquinolines; K562 Cells; Leigh Disease; Mice; Mice, Knockout; Mitochondria; Oxygen; Respiration; Suppression, Genetic; Von Hippel-Lindau Tumor Suppressor Protein; Zebrafish