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J. Biol. Chem., Vol. 280, Issue 22, 21673-21679, June 3, 2005

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Cytokines Induce Nitric Oxide-mediated mtDNA Damage and Apoptosis in Oligodendrocytes

PROTECTIVE ROLE OF TARGETING 8-OXOGUANINE GLYCOSYLASE TO MITOCHONDRIA^*

Nadiya M. Druzhyna, Sergyi I. Musiyenko, Glenn L. Wilson, and Susan P. LeDoux

From the Department of Cell Biology and Neuroscience, College of Medicine, University of South Alabama, Mobile, Alabama 36688

Nitric oxide (NO) that is produced by inducible NO synthase (iNOS) in glial cells is thought to contribute significantly to the pathogenesis of multiple sclerosis. Oligodendrocytes can be stimulated to express iNOS by inflammatory cytokines, which are known to accumulate in the multiple sclerotic brain. The potentially pathological levels of NO produced under these circumstances can target a wide spectrum of intracellular components. We hypothesized that one of the critical targets for damage that leads to disease is mtDNA. In this study, we found that cytokines, in particular a combination of tumor necrosis factor- (50 ng/ml) and IFN (25 ng/ml), cause elevated NO production in primary cultures of rat oligodendrocytes. Western blot analysis revealed a strong enhancement of iNOS expression 48 h after cytokine treatment. Within the same time period, NO-mediated mtDNA damage was shown by Southern blot analysis and by ligation-mediated PCR. Targeting the DNA repair enzyme human 8-oxoguanine DNA glycosylase (hOGG1) to the mitochondria of oligodendrocytes had a protective effect against this cytokine-mediated mtDNA damage. Moreover, it was shown that mitochondrial transport sequence hOGG1-transfected oligodendrocytes had fewer apoptotic cells compared with cells containing vector only following treatment with the cytokines. Subsequent experiments revealed that targeting hOGG1 to mitochondria reduces the activation of caspase-9, showing that this recombinant protein works to reduce apoptosis that is occurring through a mitochondria-based pathway.

Received for publication, October 12, 2004 , and in revised form, March 9, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Cell Biology and Neuroscience, University of South Alabama, MSB 1200, Mobile, AL 36688. Tel.: 251-460-6762; Fax: 251-414-8241; E-mail: sledoux{at}usouthal.edu.

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