nNOS mediated mitochondrial injury in LPS stimulated oligodendrocytes.

Yao SY, Natarajan C, Sriram S
Mitochondrion. 2012 12 (2): 336-44

PMID: 22289618 · DOI:10.1016/j.mito.2012.01.002

Products of inflammation and the activation of nitric oxide synthase have been proposed as a mechanism of oligodendrocyte injury in CNS inflammation. There are currently three well described and known isoforms of NOS. Of these, neuronal NOS (nNOS) was initially discovered in neurons, endothelial NOS (eNOS) in vascular endothelium, while the inducible form of NOS (iNOS) is known to be activated in oligodendrocytes, astrocytes and microglia. We examined the activation of nNOS and the down stream effects of NO production in oligodendrocyte precursor cells (OPC) and MO3.13 cell line following culture with LPS. Our studies show that both MO3.13 cells and OPC are susceptible to the cellular injury resulting from LPS mediated activation and NO production. Activation of the TLR4 receptor with LPS led to decrease in cell viability that was associated with loss of mitochondrial membrane potential and impaired enzymatic activity of complex I and complex IV protein of the respiratory chain. 7-NI, a known inhibitor of nNOS was able to rescue of cells from LPS mediated mitochondrial damage. Loss of mitochondrial function was associated with translocation of cytochrome C and apoptosis inducing factor to the cytosol, setting the stage for apoptosis. Phosphorylation of PI3K and Akt was required for optimal activation of NOS. These studies provide a biochemical basis for nNOS mediated oligodendrocyte injury and suggest similar mechanisms may play a role in diseases characterized by oligodendrocyte loss and demyelination.

Copyright © 2012 Elsevier B.V. and Mitochondria Research Society. All rights reserved. All rights reserved.

MeSH Terms (14)

Animals Apoptosis Cells, Cultured Cell Survival Cytochromes c Electron Transport Complex I Electron Transport Complex IV Lipopolysaccharides Membrane Potential, Mitochondrial Mitochondria Nitric Oxide Synthase Oligodendroglia Rats Rats, Sprague-Dawley

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