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

Isha H Jain; Luca Zazzeron; Olga Goldberger; Eizo Marutani; Gregory R Wojtkiewicz; Tslil Ast; Hong Wang; Grigorij Schleifer; Anna Stepanova; Kathleen Brepoels; Luc Schoonjans; Peter Carmeliet; Alexander Galkin; Fumito Ichinose; Warren M Zapol; Vamsi K Mootha

doi:10.1016/j.cmet.2019.07.006

Publisher Website

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.

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. This record was last updated on 09/12/2020 and may not reflect the most current and accurate biomedical/scientific data available from NLM. The corresponding record at NLM can be accessed at https://www.ncbi.nlm.nih.gov/pubmed/31402314

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