Nicotinamide mononucleotide adenylyltransferase promotes hypoxic survival by activating the mitochondrial unfolded protein response
| Autor: | X R Mao, D M Kaufman, C M Crowder |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Paclitaxel Genetic Vectors Longevity Immunology Biology Hippocampus law.invention Animals Genetically Modified Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Genes Reporter law Mitochondrial unfolded protein response NMNAT1 Animals Nicotinamide-Nucleotide Adenylyltransferase Caenorhabditis elegans Gene Cells Cultured Loss function Cell Biology Molecular biology Cytoprotection Phenotype Axons Cell Hypoxia Mitochondria 3. Good health Oxygen 030104 developmental biology Proteostasis Unfolded Protein Response Suppressor Original Article 030217 neurology & neurosurgery |
| Zdroj: | Cell Death & Disease |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/cddis.2016.5 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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