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Title: 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 limiting 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:
 [1];  [2];  [1];  [3];  [3];  [1];  [1];  [1];  [4];  [4];  [4];  [5];  [2];  [1]
  1. Massachusetts General Hospital, Boston, MA (United States). Dept. of Molecular Biology and Howard Hughes Medical Inst.; Harvard Medical School, Boston, MA (United States). Dept. of Systems Biology; Broad Inst. of Harvard and MIT, Cambridge, MA (United States)
  2. Massachusetts General Hospital, Boston, MA (United States). Dept. of Anesthesia, Critical Care, and Pain Medicine
  3. Harvard Medical School, Boston, MA (United States). Brigham and Women's Hospital, Genetics Division
  4. Broad Inst. of Harvard and MIT, Cambridge, MA (United States); McGovern Inst. for Brain Research, Cambridge, MA (United States); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States). Dept. of Brain and Cognitive Sciences; Dept. of Biological Engineering
  5. Broad Inst. of Harvard and MIT, Cambridge, MA (United States); Harvard Medical School, Boston, MA (United States). Brigham and Women's Hospital, Genetics Division; Dana-Farber Cancer Institute, Boston, MA (United States). Gastrointestinal Cancer Center; Harvard Stem Cell Inst., Cambridge, MA (United States)
Publication Date:
Research Org.:
Krell Inst., Ames, IA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1467446
Grant/Contract Number:  
FG02-97ER25308
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Science
Additional Journal Information:
Journal Volume: 352; Journal Issue: 6281; Journal ID: ISSN 0036-8075
Publisher:
AAAS
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Jain, Isha H., Zazzeron, Luca, Goli, Rahul, Alexa, Kristen, Schatzman-Bone, Stephanie, Dhillon, Harveen, Goldberger, Olga, Peng, Jun, Shalem, Olphir, Sanjana, Neville E., Zhang, Feng, Goessling, Wolfram, Zapol, Warren M., and Mootha, Vamsi K. Hypoxia as a therapy for mitochondrial disease. United States: N. p., 2016. Web. doi:10.1126/science.aad9642.
Jain, Isha H., Zazzeron, Luca, Goli, Rahul, Alexa, Kristen, Schatzman-Bone, Stephanie, Dhillon, Harveen, Goldberger, Olga, Peng, Jun, Shalem, Olphir, Sanjana, Neville E., Zhang, Feng, Goessling, Wolfram, Zapol, Warren M., & Mootha, Vamsi K. Hypoxia as a therapy for mitochondrial disease. United States. doi:10.1126/science.aad9642.
Jain, Isha H., Zazzeron, Luca, Goli, Rahul, Alexa, Kristen, Schatzman-Bone, Stephanie, Dhillon, Harveen, Goldberger, Olga, Peng, Jun, Shalem, Olphir, Sanjana, Neville E., Zhang, Feng, Goessling, Wolfram, Zapol, Warren M., and Mootha, Vamsi K. Thu . "Hypoxia as a therapy for mitochondrial disease". United States. doi:10.1126/science.aad9642. https://www.osti.gov/servlets/purl/1467446.
@article{osti_1467446,
title = {Hypoxia as a therapy for mitochondrial disease},
author = {Jain, Isha H. and Zazzeron, Luca and Goli, Rahul and Alexa, Kristen and Schatzman-Bone, Stephanie and Dhillon, Harveen and Goldberger, Olga and Peng, Jun and Shalem, Olphir and Sanjana, Neville E. and Zhang, Feng and Goessling, Wolfram and Zapol, Warren M. and Mootha, Vamsi K.},
abstractNote = {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 limiting 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.},
doi = {10.1126/science.aad9642},
journal = {Science},
number = 6281,
volume = 352,
place = {United States},
year = {Thu Feb 25 00:00:00 EST 2016},
month = {Thu Feb 25 00:00:00 EST 2016}
}

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Works referenced in this record:

Genome-Scale CRISPR-Cas9 Knockout Screening in Human Cells
journal, December 2013

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