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
  • Anaerobiosis
  • Animals
  • Antimycin A/analogs & derivatives
  • Antimycin A/pharmacology
  • Bacterial Proteins
  • Biomarkers/blood
  • Body Temperature
  • Body Weight
  • Disease Models, Animal
  • Electron Transport/drug effects
  • Electron Transport Complex I/genetics
  • Endonucleases
  • Energy Metabolism/drug effects
  • Energy Metabolism/genetics
  • Gene Knockout Techniques
  • Genome-Wide Association Study
  • Glycine/analogs & derivatives
  • Glycine/pharmacology
  • Glycine/therapeutic use
  • Humans
  • Hypoxia-Inducible Factor 1/metabolism
  • Isoquinolines/pharmacology
  • Isoquinolines/therapeutic use
  • K562 Cells
  • Leigh Disease/genetics*
  • Leigh Disease/pathology
  • Leigh Disease/therapy*
  • Mice
  • Mice, Knockout
  • Mitochondria/drug effects
  • Mitochondria/metabolism*
  • Oxygen/metabolism*
  • Respiration
  • Suppression, Genetic
  • Von Hippel-Lindau Tumor Suppressor Protein/antagonists & inhibitors
  • Von Hippel-Lindau Tumor Suppressor Protein/genetics*
  • Zebrafish
PubMed
26917594 Full text @ Science
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
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping