RRC ID 53470
Author Mao XR, Kaufman DM, Crowder CM.
Title Nicotinamide mononucleotide adenylyltransferase promotes hypoxic survival by activating the mitochondrial unfolded protein response.
Journal Cell Death Dis
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.
Volume 7(2)
Pages e2113
Published 2016-2-25
DOI 10.1038/cddis.2016.5
PII cddis20165
PMID 26913604
PMC PMC4849163
MeSH Animals Animals, Genetically Modified / metabolism Axons / metabolism Caenorhabditis elegans / metabolism Cell Hypoxia Cells, Cultured Genes, Reporter Genetic Vectors / metabolism Hippocampus / cytology Hippocampus / metabolism Longevity Mice Mitochondria / metabolism* Nicotinamide-Nucleotide Adenylyltransferase / genetics Nicotinamide-Nucleotide Adenylyltransferase / metabolism* Oxygen / metabolism Paclitaxel / pharmacology Phenotype Unfolded Protein Response* / drug effects
IF 6.304
Times Cited 11
C.elegans tm843