title: Nicotinamide mononucleotide adenylyltransferase promotes hypoxic survival by activating the mitochondrial unfolded protein response.
abstract: Gain-of-function mutations in the mouse nicotinamide mononucleotide adenylyltransferase type 1 (Nmnat1) produce two remarkable phenotypes: protection against traumatic axonal degeneration and reduced hypoxic brain injury. Despite intensive efforts, the mechanism of Nmnat1 cytoprotection remains elusive. To develop a new model to define this mechanism, we heterologously expressed a mouse Nmnat1 non-nuclear-localized gain-of-function mutant gene (m-nonN-Nmnat1) in the nematode Caenorhabditis elegans and show that it provides protection from both hypoxia-induced animal death and taxol-induced axonal pathology. Additionally, we find that m-nonN-Nmnat1 significantly lengthens C. elegans lifespan. Using the hypoxia-protective phenotype in C. elegans, we performed a candidate screen for genetic suppressors of m-nonN-Nmnat1 cytoprotection. Loss of function in two genes, haf-1 and dve-1, encoding mitochondrial unfolded protein response (mitoUPR) factors were identified as suppressors. M-nonN-Nmnat1 induced a transcriptional reporter of the mitoUPR gene hsp-6 and provided protection from the mitochondrial proteostasis toxin ethidium bromide. M-nonN-Nmnat1 was also protective against axonal degeneration in C. elegans induced by the chemotherapy drug taxol. Taxol markedly reduced basal expression of a mitoUPR reporter; the expression was restored by m-nonN-Nmnat1. Taken together, these data implicate the mitoUPR as a mechanism whereby Nmnat1 protects from hypoxic and axonal injury.
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
authors.forename: X R
authors.initials: XR
authors.lastname: Mao
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.|Medical Scientist Training Program, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.|Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195-6540, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Kaufman
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.|Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195-6540, USA.|Department of Genome Sciences, University of Washington School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195-6540, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Crowder
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000378:metabolism; D001369:Axons / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D008136:Longevity; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D010641:Phenotype; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D009612:Nicotinamide-Nucleotide Adenylyltransferase; C510972:Nmnat1 protein, mouse; D017239:Paclitaxel; D010100:Oxygen