論文 - 詳細
| RRC ID | 53470 |
|---|---|
| 著者 | Mao XR, Kaufman DM, Crowder CM. |
| タイトル | Nicotinamide mononucleotide adenylyltransferase promotes hypoxic survival by activating the mitochondrial unfolded protein response. |
| ジャーナル | 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. |
| 巻・号 | 7(2) |
| ページ | e2113 |
| 公開日 | 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 |
| 引用数 | 11 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 4 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm843 |