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Leigh Syndrome Mouse Model Can Be Rescued by Interventions that Normalize Brain Hyperoxia, but Not HIF Activation.

Authors
  • Jain, Isha H1
  • Zazzeron, Luca2
  • Goldberger, Olga1
  • Marutani, Eizo2
  • Wojtkiewicz, Gregory R3
  • Ast, Tslil1
  • Wang, Hong1
  • Schleifer, Grigorij2
  • Stepanova, Anna4
  • Brepoels, Kathleen5
  • Schoonjans, Luc5
  • Carmeliet, Peter5
  • Galkin, Alexander4
  • Ichinose, Fumito2
  • Zapol, Warren M6
  • Mootha, Vamsi K7
  • 1 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.
  • 2 Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • 3 Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • 4 Department of Pediatrics, Division of Neonatology, Columbia University, New York, NY, USA.
  • 5 Laboratory of Angiogenesis and Vascular Metabolism, VIB-KU Leuven, Center for Cancer Biology, Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium. , (Belgium)
  • 6 Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA. Electronic address: [email protected]
  • 7 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. Electronic address: [email protected]
Type
Published Article
Journal
Cell metabolism
Publication Date
Oct 01, 2019
Volume
30
Issue
4
Identifiers
DOI: 10.1016/j.cmet.2019.07.006
PMID: 31402314
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Leigh syndrome is a devastating mitochondrial disease for which there are no proven therapies. We previously showed that breathing chronic, continuous hypoxia can prevent and even reverse neurological disease in the Ndufs4 knockout (KO) mouse model of complex I (CI) deficiency and Leigh syndrome. Here, we show that genetic activation of the hypoxia-inducible factor transcriptional program via any of four different strategies is insufficient to rescue disease. Rather, we observe an age-dependent decline in whole-body oxygen consumption. These mice exhibit brain tissue hyperoxia, which is normalized by hypoxic breathing. Alternative experimental strategies to reduce oxygen delivery, including breathing carbon monoxide (600 ppm in air) or severe anemia, can reverse neurological disease. Therefore, unused oxygen is the most likely culprit in the pathology of this disease. While pharmacologic activation of the hypoxia response is unlikely to alleviate disease in vivo, interventions that safely normalize brain tissue hyperoxia may hold therapeutic potential. Copyright © 2019. Published by Elsevier Inc.

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