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

Gregory S. McElroy, Colleen R. Reczek, Paul A. Reyfman, Divakar S. Mithal, Craig M. Horbinski, Navdeep S. Chandel*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)301-308.e6
JournalCell Metabolism
Volume32
Issue number2
DOIs
StatePublished - Aug 4 2020

Keywords

  • Leigh syndrome
  • NAD
  • ataxia
  • metabolism
  • microglia
  • mitochondria
  • mitochondrial complex I
  • mitochondrial disease
  • neurodegeneration
  • neurometabolism

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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