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

24 Pages Posted: 16 Sep 2019 Sneak Peek Status: Review Complete

See all articles by Greg McElroy

Greg McElroy

Northwestern University - Division of Pulmonary and Critical Care Medicine

Colleen Reczek

Northwestern University - Division of Pulmonary and Critical Care Medicine

Paul Reyfman

Northwestern University - Division of Pulmonary and Critical Care Medicine

Divaker Mithal

Northwestern University - Division of Pulmonary and Critical Care Medicine

Craig Horbinski

Northwestern University - Department of Neurological Surgery

Navdeep Chandel

Northwestern University - Division of Pulmonary and Critical Care Medicine

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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, 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.

Keywords: Mitochondria, neurodegeneration, NAD

Suggested Citation

McElroy, Greg and Reczek, Colleen and Reyfman, Paul and Mithal, Divaker and Horbinski, Craig and Chandel, Navdeep, NAD+ Regeneration Rescues Lifespan But Not Ataxia in a Mouse Model of Brain Mitochondrial Complex I Dysfunction (September 12, 2019). CELL-METABOLISM-D-19-01020. Available at SSRN: https://ssrn.com/abstract=3452783 or http://dx.doi.org/10.2139/ssrn.3452783
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Greg McElroy

Northwestern University - Division of Pulmonary and Critical Care Medicine

United States

Colleen Reczek

Northwestern University - Division of Pulmonary and Critical Care Medicine

United States

Paul Reyfman

Northwestern University - Division of Pulmonary and Critical Care Medicine

United States

Divaker Mithal

Northwestern University - Division of Pulmonary and Critical Care Medicine

United States

Craig Horbinski

Northwestern University - Department of Neurological Surgery

Chicago, IL 60611
United States

Navdeep Chandel (Contact Author)

Northwestern University - Division of Pulmonary and Critical Care Medicine

United States

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