Jain et al. performed a genome-wide, Cas9-mediated screen using the human leukemic suspension cell line, K562, to identify factors that are protective during mitochondrial respiratory chain (RC) inhibition.
Hypoxia response, an endogenous program evolved to adapt to limiting oxygen availability, was a very interesting finding.
Genetic or small molecule activation of the hypoxia response appears to be protective against mitochondrial toxicity in cultured cells and zebrafish models. Marked improvement was noted in survival, body weight and temperature, behavior, neuropathology and disease biomarkers in a genetic mouse model of Leigh syndrome.
The preclinical studies described by Jain et al. support that hypoxic gas mixtures may be useful in the management of mitochondrial disorders. Hypoxia activates an adaptive response that allows mammals to cope with limiting oxygen levels, thus decreasing the reliance on mitochondrial oxidative metabolism. Given, in mitochondrial disease the hypoxia signal is not present, this adaptive response is not necessarily activated.
This study raises the possibility of hypoxic gas mixtures as a potential therapeutic approach for patients with mitochondrial disease. Interestingly, the current study has utilized a chronic 11% inspired oxygen and healthy humans can reportedly acclimate to high altitudes where oxygen availability is comparable to that used in the experiments.
Before the chronic hypoxia strategy described here can be evaluated in the clinical setting, additional pre-clinical studies are needed to establish its safety, efficacy and generalizability.
Hypoxia as a therapy for mitochondrial disease. Jain IH, Zazzeron L, Goli R, Alexa K, Schatzman-Bone S, Dhillon H, Goldberger O, Peng J, Shalem O, Sanjana NE, Zhang F, Goessling W, Zapol WM, Mootha VK. Science. 2016 Feb 25. pii: aad9642. PMID: 26917594
posted by Yannis Trakadis, MD