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

Cell Metab. 2019 Oct 1;30(4):824-832.e3. doi: 10.1016/j.cmet.2019.07.006. Epub 2019 Aug 8.


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.

Keywords: Leigh syndrome; anemia; carbon monoxide; hemoglobin; hyperoxia; hypoxia; mitochondria; oxygen; therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia / metabolism
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Brain / metabolism*
  • Brain / pathology
  • Carbon Monoxide / therapeutic use*
  • Disease Models, Animal
  • Hyperoxia / metabolism
  • Hyperoxia / therapy*
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1 / genetics
  • Hypoxia-Inducible Factor 1 / metabolism
  • Leigh Disease / metabolism
  • Leigh Disease / therapy*
  • Mice
  • Oxygen / metabolism*


  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1
  • endothelial PAS domain-containing protein 1
  • Carbon Monoxide
  • Oxygen

Supplementary concepts

  • Leigh Syndrome Due To Mitochondrial Complex I Deficiency