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NAD+ regeneration rescues lifespan but not ataxia in a mouse model of brain mitochondrial complex I dysfunction

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 is the dominant function of mitochondrial complex I in protection from brain pathology. We generated a mouse that conditionally expresses the yeast NDI1 protein, 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. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE149616 | GEO | 2020/04/30

REPOSITORIES: GEO

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NAD+ regeneration rescues lifespan but not ataxia in a mouse model of brain mitochondrial complex I dysfunction

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