2. Academic Validation
  3. Hypoxia as a therapy for mitochondrial disease

Hypoxia as a therapy for mitochondrial disease

  • Science. 2016 Apr 1;352(6281):54-61. doi: 10.1126/science.aad9642.
Isha H Jain 1,  Luca Zazzeron 2,  Rahul Goli 1,  Kristen Alexa 3,  Stephanie Schatzman-Bone 3,  Harveen Dhillon 1,  Olga Goldberger 1,  Jun Peng 1,  Ophir Shalem 4,  Neville E Sanjana 4,  Feng Zhang 4,  Wolfram Goessling 5,  Warren M Zapol 2,  Vamsi K Mootha 6
Affiliations

Affiliations

  • 1 Department of Molecular Biology and Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA, USA. Department of Systems Biology, Harvard Medical School, Boston, MA, USA. Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 2 Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • 3 Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 4 Broad Institute of Harvard and MIT, Cambridge, MA, USA. McGovern Institute for Brain Research, Cambridge, MA, USA. Department of Brain and Cognitive Sciences and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 5 Broad Institute of Harvard and MIT, Cambridge, MA, USA. Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Stem Cell Institute, Cambridge, MA, USA.
  • 6 Department of Molecular Biology and Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA, USA. Department of Systems Biology, Harvard Medical School, Boston, MA, USA. Broad Institute of Harvard and MIT, Cambridge, MA, USA. vamsi@hms.harvard.edu.
PMID: 26917594 DOI: 10.1126/science.aad9642
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.

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