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 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.
authors.affiliation: 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.
authors.forename: Isha H
authors.initials: IH
authors.lastname: Jain
authors.affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Zazzeron
authors.affiliation: 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.
authors.forename: Rahul
authors.initials: R
authors.lastname: Goli
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Alexa
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schatzman-Bone
authors.affiliation: 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.
authors.forename: Harveen
authors.initials: H
authors.lastname: Dhillon
authors.affiliation: 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.
authors.forename: Olga
authors.initials: O
authors.lastname: Goldberger
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
authors.affiliation: 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.
authors.forename: Ophir
authors.initials: O
authors.lastname: Shalem
authors.affiliation: 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.
authors.forename: Neville E
authors.initials: NE
authors.lastname: Sanjana
authors.affiliation: 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.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Goessling
authors.affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Warren M
authors.initials: WM
authors.lastname: Zapol
authors.affiliation: 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.
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Mootha
mesh_terms: D000693:Anaerobiosis; D000818:Animals; D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology; D001426:Bacterial Proteins; D015415:Biomarkers / Q000097:blood; D001831:Body Temperature; D001835:Body Weight; D000076987:CRISPR-Associated Protein 9; D004195:Disease Models, Animal; D004579:Electron Transport / Q000187:drug effects; D042967:Electron Transport Complex I / Q000235:genetics; D004720:Endonucleases; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D055786:Gene Knockout Techniques; D055106:Genome-Wide Association Study; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use; D020014:K562 Cells; D007888:Leigh Disease / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D012119:Respiration; D013489:Suppression, Genetic; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D015027:Zebrafish
chemical_list: D001426:Bacterial Proteins; D015415:Biomarkers; D051793:Hypoxia-Inducible Factor 1; D007546:Isoquinolines; C534449:Ndufs4 protein, mouse; C032456:antimycin; D000968:Antimycin A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000076987:CRISPR-Associated Protein 9; C000606107:Cas9 endonuclease Streptococcus pyogenes; D004720:Endonucleases; D042967:Electron Transport Complex I; D010100:Oxygen; D005998:Glycine; C584543:roxadustat