NAD+ Regeneration Rescues Lifespan, but Not Ataxia, in a Mouse Model of Brain Mitochondrial Complex I Dysfunction
Gregory S McElroy1, Colleen R Reczek1, Paul A Reyfman1, Divakar S Mithal2, Craig M Horbinski3, Navdeep S Chandel4
- Northwestern University Feinberg School of Medicine, Department of Medicine Division of Pulmonary and Critical Care Medicine, Chicago, IL 60611, USA.
- 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.
- 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.
- 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