Hypoxia as a therapy for mitochondrial disease.

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.

• Authors: Isha H Jain, Luca Zazzeron, Rahul Goli, Kristen Alexa, Stephanie Schatzman-Bone, Harveen Dhillon, Olga Goldberger, Jun Peng, Ophir Shalem, Neville E Sanjana, Feng Zhang, Wolfram Goessling, Warren M Zapol, Vamsi K Mootha
• Journal: Science (New York, N.Y.) (Science) Vol. 352 Issue 6281 Pg. 54-61 (Apr 01 2016) ISSN: 1095-9203 [Electronic] United States
• PMID: 26917594 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2016, American Association for the Advancement of Science.

Chemical References

• Bacterial Proteins
• Biomarkers
• 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
• roxadustat

Topics

• Anaerobiosis
• Animals
• Antimycin A (analogs & derivatives, 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, genetics)
• Gene Knockout Techniques
• Genome-Wide Association Study
• Glycine (analogs & derivatives, pharmacology, therapeutic use)
• Humans
• Hypoxia-Inducible Factor 1 (metabolism)
• Isoquinolines (pharmacology, therapeutic use)
• K562 Cells
• Leigh Disease (genetics, pathology, therapy)
• Mice
• Mice, Knockout
• Mitochondria (drug effects, metabolism)
• Oxygen (metabolism)
• Respiration
• Suppression, Genetic
• Von Hippel-Lindau Tumor Suppressor Protein (antagonists & inhibitors, genetics)
• Zebrafish