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Hypoxia as a therapy for mitochondrial disease.
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.
Afiliação
  • Jain IH; 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.
  • Zazzeron L; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Goli R; 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.
  • Alexa K; Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Schatzman-Bone S; Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Dhillon H; 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.
  • Goldberger O; 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.
  • Peng J; 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.
  • Shalem O; 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.
  • Sanjana NE; 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.
  • Zhang F; 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.
  • Goessling W; 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.
  • Zapol WM; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Mootha VK; 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.
Science ; 352(6281): 54-61, 2016 Apr 01.
Article em En | MEDLINE | ID: mdl-26917594
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxigênio / Doença de Leigh / Proteína Supressora de Tumor Von Hippel-Lindau / Mitocôndrias Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2016 Tipo de documento: Article
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxigênio / Doença de Leigh / Proteína Supressora de Tumor Von Hippel-Lindau / Mitocôndrias Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2016 Tipo de documento: Article