Publication Date:
2016-02-27
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860742/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860742/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- 1R01-MH110049/MH/NIMH NIH HHS/ -- 5DP1-MH100706/DP/NCCDPHP CDC HHS/ -- 5R01DK097768-03/DK/NIDDK NIH HHS/ -- DP1 MH100706/MH/NIMH NIH HHS/ -- K99 HG008171/HG/NHGRI NIH HHS/ -- K99-HG008171/HG/NHGRI NIH HHS/ -- R01 DK090311/DK/NIDDK NIH HHS/ -- R01 DK097768/DK/NIDDK NIH HHS/ -- R01 MH110049/MH/NIMH NIH HHS/ -- R01DK090311/DK/NIDDK NIH HHS/ -- R24 OD017870/OD/NIH HHS/ -- R24OD017870/OD/NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Apr 1;352(6281):54-61. doi: 10.1126/science.aad9642. Epub 2016 Feb 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA. ; Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ; 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. ; 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. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26917594" target="_blank"〉PubMed〈/a〉
Keywords:
Anaerobiosis
;
Animals
;
Antimycin A/analogs & derivatives/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/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
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
