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 language | English (US) |
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Pages (from-to) | 301-308.e6 |
Journal | Cell Metabolism |
Volume | 32 |
Issue number | 2 |
DOIs | |
State | Published - 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