Hypoxia as a Therapy for Mitochondrial Disease

Details

• Alternative Title:
  Science
• Personal Author:
  Jain, Isha H. ; Zazzeron, Luca ; Goli, Rahul ; Alexa, Kristen ; Schatzman-Bone, Stephanie ; Dhillon, Harveen ; Goldberger, Olga ; Peng, Jun ; Shalem, Ophir ; Sanjana, Neville E. ; Zhang, Feng ; Goessling, Wolfram ; Zapol, Warren M. ; Mootha, Vamsi K.
• Description:
  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.
• Subjects:
  Anaerobiosis Animals Antimycin A Article Bacterial Proteins Biomarkers Body Temperature Body Weight CRISPR-Associated Protein 9 Disease Models, Animal Electron Transport Electron Transport Complex I Endonucleases Energy Metabolism Gene Knockout Techniques Genome-Wide Association Study Glycine Humans Hypoxia-Inducible Factor 1 Isoquinolines K562 Cells Leigh Disease Mice Mice, Knockout Mitochondria Oxygen Respiration Suppression, Genetic Von Hippel-Lindau Tumor Suppressor Protein Zebrafish

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• Source:
  Science. 352(6281):54-61
• Pubmed ID:
  26917594
• Pubmed Central ID:
  PMC4860742
• Document Type:
  Journal Article
• Funding:
  R01DK090311/DK/NIDDK NIH HHS/United States ; R24 OD017870/OD/NIH HHS/United States ; R01 MH110049/MH/NIMH NIH HHS/United States ; P30 DK043351/DK/NIDDK NIH HHS/United States ; K99 HG008171/HG/NHGRI NIH HHS/United States ; 5DP1-MH100706/DP/NCCDPHP CDC HHS/United States ; K99-HG008171/HG/NHGRI NIH HHS/United States ; 1R01-MH110049/MH/NIMH NIH HHS/United States ; DP1 MH100706/MH/NIMH NIH HHS/United States ; Howard Hughes Medical Institute/United States ; R01 DK097768/DK/NIDDK NIH HHS/United States ; 5R01DK097768-03/DK/NIDDK NIH HHS/United States ; R01 DK090311/DK/NIDDK NIH HHS/United States ; R24OD017870/OD/NIH HHS/United States
• Volume:
  352
• Issue:
  6281
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:e87414d2948dfdf175d9fd3bb7fa1274c716f01a39f3aba45ab46c10e792bf91
• Download URL:
  https://stacks.cdc.gov/view/cdc/39440/cdc_39440_DS1.pdf
• File Type:
  [PDF - 1.28 MB ]