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

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2020 Jun 24

PMID 32574562

Citations 45

Authors

Gregory S McElroy

Colleen R Reczek

Paul A Reyfman

Divakar S Mithal

Craig M Horbinski

Navdeep S Chandel

Affiliations

Soon will be listed here.

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.

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