期刊
SCIENCE
卷 352, 期 6281, 页码 54-61出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aad9642
关键词
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资金
- Department of Energy Computational Science Graduate Fellowship Program [DE-FG02-97ER25308]
- National Institutes of Health (NIH) through a NHGRI [K99-HG008171]
- Simons Center for the Social Brain at the Massachusetts Institute of Technology
- NIH through NIMH [5DP1-MH100706, 1R01-MH110049]
- NIDDK [5R01DK097768-03]
- NSF
- New York Stem Cell
- Simons, Paul G. Allen Family Foundation
- Vallee Foundation
- NIH [R01DK090311, R24OD017870]
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.
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