PUBLICATION
Hypoxia as a therapy for mitochondrial disease
- Authors
- Jain, I.H., Zazzeron, L., Goli, R., Alexa, K., Schatzman-Bone, S., Dhillon, H., Goldberger, O., Peng, J., Shalem, O., Sanjana, N.E., Zhang, F., Goessling, W., Zapol, W.M., Mootha, V.K.
- ID
- ZDB-PUB-160227-2
- Date
- 2016
- Source
- Science (New York, N.Y.) 352(6281): 54-61 (Journal)
- Registered Authors
- Goessling, Wolfram, Schatzman-Bone, Steph
- Keywords
- none
- MeSH Terms
-
- Endonucleases
- Electron Transport Complex I/genetics
- Suppression, Genetic
- Respiration
- Animals
- Genome-Wide Association Study
- Energy Metabolism/drug effects
- Energy Metabolism/genetics
- Mice, Knockout
- Electron Transport/drug effects
- Anaerobiosis
- Leigh Disease/genetics*
- Leigh Disease/pathology
- Leigh Disease/therapy*
- Disease Models, Animal
- Glycine/analogs & derivatives
- Glycine/pharmacology
- Glycine/therapeutic use
- Von Hippel-Lindau Tumor Suppressor Protein/antagonists & inhibitors
- Von Hippel-Lindau Tumor Suppressor Protein/genetics*
- Mitochondria/drug effects
- Mitochondria/metabolism*
- Mice
- Biomarkers/blood
- Antimycin A/analogs & derivatives
- Antimycin A/pharmacology
- Oxygen/metabolism*
- Gene Knockout Techniques
- Humans
- Body Weight
- Zebrafish
- K562 Cells
- Hypoxia-Inducible Factor 1/metabolism
- Bacterial Proteins
- Body Temperature
- Isoquinolines/pharmacology
- Isoquinolines/therapeutic use
- PubMed
- 26917594 Full text @ Science
Citation
Jain, I.H., Zazzeron, L., Goli, R., Alexa, K., Schatzman-Bone, S., Dhillon, H., Goldberger, O., Peng, J., Shalem, O., Sanjana, N.E., Zhang, F., Goessling, W., Zapol, W.M., Mootha, V.K. (2016) Hypoxia as a therapy for mitochondrial disease. Science (New York, N.Y.). 352(6281):54-61.
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 limiting 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping