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

Cell Metab. 2020 Jun 16;S1550-4131(20)30304-1. doi: 10.1016/j.cmet.2020.06.003. | PubMed

Gregory S McElroy¹, Colleen R Reczek¹, Paul A Reyfman¹, Divakar S Mithal², Craig M Horbinski³, Navdeep S Chandel⁴

1. Northwestern University Feinberg School of Medicine, Department of Medicine Division of Pulmonary and Critical Care Medicine, Chicago, IL 60611, USA.
2. Ann and Robert H. Lurie Children's Hospital of Chicago, Pediatric Neurology, Chicago, IL 60611, USA; Northwestern University Feinberg School of Medicine, Department of Pediatrics, Chicago, IL 60611, USA.
3. Northwestern University Feinberg School of Medicine, Department of Pathology, Chicago, IL 60611, USA; Northwestern University Feinberg School of Medicine, Department of Neurological Surgery, Chicago, IL 60611, USA.
4. Northwestern University Feinberg School of Medicine, Department of Medicine Division of Pulmonary and Critical Care Medicine, Chicago, IL 60611, USA; Northwestern University Feinberg School of Medicine, Department of Biochemistry and Molecular Genetics, Chicago, IL 60611, USA. Electronic address: nav@northwestern.edu.

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.

Presented By Gregory McElroy