@article{812c16bc910e443d93f4e5ece7892ff1,
title = "NAD+ Regeneration Rescues Lifespan, but Not Ataxia, in a Mouse Model of Brain Mitochondrial Complex I Dysfunction",
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.",
keywords = "Leigh syndrome, NAD, ataxia, metabolism, microglia, mitochondria, mitochondrial complex I, mitochondrial disease, neurodegeneration, neurometabolism",
author = "McElroy, {Gregory S.} and Reczek, {Colleen R.} and Reyfman, {Paul A.} and Mithal, {Divakar S.} and Horbinski, {Craig M.} and Chandel, {Navdeep S.}",
note = "Funding Information: We thank the following core facilities at Northwestern: Transgenic and Targeted Mutagenesis Laboratory, CTI Small Animal Imaging Core, Behavioral Phenotyping Core, Pulmonary NextGen Sequencing Core, RHLCCC Metabolomics Core, Center for Advanced Microscopy, and RHLCCC Flow Cytometry Core Facility. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the RHLCC. We thank Michele Hadhazy and Elizabeth McNally for the use of Whole-Body Plethysmography. We thank the Center for Comparative Medicine staff. We thank Elizabeth Bartom for the use of the Ceto pipeline. We thank Eric Dufour from the University of Tampere for NDI1 antibody. Funding for this project was provided by the following NIH grants: NIH2PO1HL071643-11A1 , NIH1R35CA197532-01 , and NIH1PO1AG049665-01 to N.S.C.; NIH/ NCI T32CA09560 to G.S.M.; NHLBI T32 HL076139-11 to C.R.R.; NHLBI F32HL136111 to P.A.R.; NINDS R25 NS070695 to D.S.M.; and K08CA155764 and R01NS102669 to C.M.H. P.A.R. was supported by an American Thoracic Society/Boehringer Ingelheim Partner grant. Funding Information: We thank the following core facilities at Northwestern: Transgenic and Targeted Mutagenesis Laboratory, CTI Small Animal Imaging Core, Behavioral Phenotyping Core, Pulmonary NextGen Sequencing Core, RHLCCC Metabolomics Core, Center for Advanced Microscopy, and RHLCCC Flow Cytometry Core Facility. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the RHLCC. We thank Michele Hadhazy and Elizabeth McNally for the use of Whole-Body Plethysmography. We thank the Center for Comparative Medicine staff. We thank Elizabeth Bartom for the use of the Ceto pipeline. We thank Eric Dufour from the University of Tampere for NDI1 antibody. Funding for this project was provided by the following NIH grants: NIH2PO1HL071643-11A1, NIH1R35CA197532-01, and NIH1PO1AG049665-01 to N.S.C.; NIH/NCI T32CA09560 to G.S.M.; NHLBI T32 HL076139-11 to C.R.R.; NHLBI F32HL136111 to P.A.R.; NINDS R25 NS070695 to D.S.M.; and K08CA155764 and R01NS102669 to C.M.H. P.A.R. was supported by an American Thoracic Society/Boehringer Ingelheim Partner grant. Conceptualization, G.S.M. D.S.M. C.M.H. and N.S.C.; Funding Acquisition, N.S.C.; Investigation, G.S.M. C.R.R. P.A.R. D.S.M. and C.M.H.; Supervision, C.M.H. and N.S.C.; Visualization, G.S.M. C.R.R. and P.A.R.; Writing ? Original Draft, G.S.M.; Writing ? Review & Editing, G.S.M. C.R.R. P.A.R. C.M.H. and N.S.C. N.S.C. is on the SAB of Raphael Pharmaceuticals. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = aug,
day = "4",
doi = "10.1016/j.cmet.2020.06.003",
language = "English (US)",
volume = "32",
pages = "301--308.e6",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "2",
}