Glutathione metabolism links FOXRED1 to NADH:ubiquinone oxidoreductase (complex I) deficiency: A hypothesis

Mitochondrion. 2015 Sep:24:105-12. doi: 10.1016/j.mito.2015.07.009. Epub 2015 Jul 30.

Abstract

FOXRED1 mutations result in complex I (NADH:ubiquinone oxidoreductase) deficiencies and Leigh syndrome (subacute necrotizing encephalomyelopathy). FOXRED1 is a mitochondrial flavoprotein related to N-methyl amino acid dehydrogenases. How is FOXRED1 required for the biogenesis of complex I? I present a hypothesis that suggests FOXRED1 catalytic activity as a sarcosine oxidase protects the developing fetus from oxidative stress during pregnancy. Loss of FOXRED1, coupled with protein, choline and/or folate-deficient diets results in the depletion of glutathione, the dysregulation of nitric oxide metabolism and the peroxynitrite-mediated inactivation of complex I.

Keywords: Glutathione metabolism; Leigh syndrome; NADH:ubiquinone oxidoreductase; Nitric oxide; S nitrosylation; Sarcosine oxidase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Electron Transport Complex I / metabolism*
  • Female
  • Glutathione / metabolism*
  • Humans
  • Leigh Disease / pathology*
  • Leigh Disease / physiopathology*
  • Molecular Chaperones / metabolism*
  • Pregnancy

Substances

  • FOXRED1 protein, human
  • Molecular Chaperones
  • Electron Transport Complex I
  • Glutathione