Hypoxia as a therapy for mitochondrial disease
Open Access
- 1 April 2016
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 352 (6281), 54-61
- https://doi.org/10.1126/science.aad9642
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.Keywords
Funding Information
- Department of Energy Computational Science (DE-FG02-97ER25308)
- National Institutes of Health (NIH) (K99-HG008171)
- Massachusetts Institute of Technology
- NIMH (5DP1-MH100706, 1R01-MH110049)
- NIDDK (5R01DK097768-03)
- Waterman Award from NSF
- New York Stem Cell
- Simons
- Paul G. Allen Family
- Vallee Foundation
- B. Metcalfe
- New York Stem Cell Foundation Robertson Investigator
- NIH (R01DK090311, R24OD017870)
- Marriott Mitochondrial Disorders Research Fund
- Howard Hughes Medical Institute
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