NAD+ Regeneration Rescues Lifespan, but Not Ataxia, in a Mouse Model of Brain Mitochondrial Complex I Dysfunction

Cell Metab. 2020 Aug 4;32(2):301-308.e6. doi: 10.1016/j.cmet.2020.06.003. Epub 2020 Jun 22.

Abstract

Mitochondrial complex I regenerates NAD+ and proton pumps for TCA cycle function and ATP production, respectively. Mitochondrial complex I dysfunction has been implicated in many brain pathologies including Leigh syndrome and Parkinson's disease. We sought to determine whether NAD+ regeneration or proton pumping, i.e., bioenergetics, is the dominant function of mitochondrial complex I in protection from brain pathology. We generated a mouse that conditionally expresses the yeast NADH dehydrogenase (NDI1), a single enzyme that can replace the NAD+ regeneration capability of the 45-subunit mammalian mitochondrial complex I without proton pumping. NDI1 expression was sufficient to dramatically prolong lifespan without significantly improving motor function in a mouse model of Leigh syndrome driven by the loss of NDUFS4, a subunit of mitochondrial complex I. Therefore, mitochondrial complex I activity in the brain supports organismal survival through its NAD+ regeneration capacity, while optimal motor control requires the bioenergetic function of mitochondrial complex I.

Keywords: Leigh syndrome; NAD; ataxia; metabolism; microglia; mitochondria; mitochondrial complex I; mitochondrial disease; neurodegeneration; neurometabolism.

Publication types

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

MeSH terms

  • Animals
  • Brain / metabolism*
  • Disease Models, Animal
  • Electron Transport Complex I / deficiency
  • Electron Transport Complex I / metabolism*
  • Female
  • Longevity*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / metabolism*
  • NAD / metabolism*
  • Saccharomyces cerevisiae / metabolism

Substances

  • NAD
  • Electron Transport Complex I