Affordable Access

deepdyve-link
Publisher Website

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

Authors
  • McElroy, Gregory S1
  • Reczek, Colleen R1
  • Reyfman, Paul A1
  • Mithal, Divakar S2
  • Horbinski, Craig M3
  • Chandel, Navdeep S4
  • 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: [email protected]
Type
Published Article
Journal
Cell metabolism
Publication Date
Aug 04, 2020
Volume
32
Issue
2
Identifiers
DOI: 10.1016/j.cmet.2020.06.003
PMID: 32574562
Source
Medline
Keywords
Language
English
License
Unknown

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. Copyright © 2020 Elsevier Inc. All rights reserved.

Report this publication

Statistics

Seen <100 times