Inhibition of oxidative metabolism by nitric oxide restricts EMCV replication selectively in pancreatic beta-cells.
J Biol Chem
; 295(52): 18189-18198, 2020 12 25.
Article
en En
| MEDLINE
| ID: mdl-33100269
ABSTRACT
Environmental factors, such as viral infection, are proposed to play a role in the initiation of autoimmune diabetes. In response to encephalomyocarditis virus (EMCV) infection, resident islet macrophages release the pro-inflammatory cytokine IL-1ß, to levels that are sufficient to stimulate inducible nitric oxide synthase (iNOS) expression and production of micromolar levels of the free radical nitric oxide in neighboring ß-cells. We have recently shown that nitric oxide inhibits EMCV replication and EMCV-mediated ß-cell lysis and that this protection is associated with an inhibition of mitochondrial oxidative metabolism. Here we show that the protective actions of nitric oxide against EMCV infection are selective for ß-cells and associated with the metabolic coupling of glycolysis and mitochondrial oxidation that is necessary for insulin secretion. Inhibitors of mitochondrial respiration attenuate EMCV replication in ß-cells, and this inhibition is associated with a decrease in ATP levels. In mouse embryonic fibroblasts (MEFs), inhibition of mitochondrial metabolism does not modify EMCV replication or decrease ATP levels. Like most cell types, MEFs have the capacity to uncouple the glycolytic utilization of glucose from mitochondrial respiration, allowing for the maintenance of ATP levels under conditions of impaired mitochondrial respiration. It is only when MEFs are forced to use mitochondrial oxidative metabolism for ATP generation that mitochondrial inhibitors attenuate viral replication. In a ß-cell selective manner, these findings indicate that nitric oxide targets the same metabolic pathways necessary for glucose stimulated insulin secretion for protection from viral lysis.
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Base de datos:
MEDLINE
Asunto principal:
Depuradores de Radicales Libres
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Islotes Pancreáticos
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Infecciones por Cardiovirus
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Virus de la Encefalomiocarditis
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Galactosa
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Glucólisis
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Óxido Nítrico
Idioma:
En
Revista:
J Biol Chem
Año:
2020
Tipo del documento:
Article