Hypoxia as a therapy for mitochondrial disease
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nihms-780675.pdf
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Author(s)
Jain, I. H.
Zazzeron, L.
Goli, R.
Alexa, K.
Schatzman-Bone, S.
Dhillon, H.
Goldberger, O.
Peng, J.
Goessling, W.
Zapol, W. M.
Date Issued
April 2016
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Jain, I. H. et al. “Hypoxia as a Therapy for Mitochondrial Disease.” Science 352, 6281 (February 2016): 54–61 © 2016 American Association for the Advancement of Science
Version
Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
McGovern Institute for Brain Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1126/science.aad9642
