Hypoxia as a therapy for mitochondrial disease

Science. 2016 Apr 1;352(6281):54-61. doi: 10.1126/science.aad9642. Epub 2016 Feb 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anaerobiosis
  • Animals
  • Antimycin A / analogs & derivatives
  • Antimycin A / pharmacology
  • Bacterial Proteins
  • Biomarkers / blood
  • Body Temperature
  • Body Weight
  • CRISPR-Associated Protein 9
  • 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

Substances

  • Bacterial Proteins
  • Biomarkers
  • FG-4592
  • Hypoxia-Inducible Factor 1
  • Isoquinolines
  • Ndufs4 protein, mouse
  • antimycin
  • Antimycin A
  • Von Hippel-Lindau Tumor Suppressor Protein
  • CRISPR-Associated Protein 9
  • Cas9 endonuclease Streptococcus pyogenes
  • Endonucleases
  • Electron Transport Complex I
  • Oxygen
  • Glycine