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J. Biol. Chem., Vol. 283, Issue 16, 10690-10697, April 18, 2008

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mt-Nd2^a Suppresses Reactive Oxygen Species Production by Mitochondrial Complexes I and III^*

Aaron M. Gusdon, Tatyana V. Votyakova, and Clayton E. Mathews¹

From the Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida 32610-0275 and the Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213

Reactive oxygen species (ROS) play a critical role in the pathogenesis of human diseases. A cytosine to adenine transversion in the mitochondrially encoded NADH dehydrogenase subunit 2 (mt-ND2, human; mt-Nd2, mouse) gene results in resistance against type 1 diabetes and several additional ROS-associated conditions. Our previous studies have demonstrated that the adenine-containing allele (mt-Nd2^a) is also strongly associated with resistance against type 1 diabetes in mice. In this report we have confirmed that the cytosine-containing allele (mt-Nd2^c) results in elevated mitochondrial ROS production. Using inhibitors of the electron transport chain, we show that when in combination with nuclear genes from the alloxan-resistant (ALR) strain, mt-Nd2^c increases ROS from complex III. Furthermore, by using alamethicin-permeabilized mitochondria, we measured a significant increase in electron transport chain-dependent ROS production from all mt-Nd2^c-encoding strains including ALR.mt^NOD, non-obese diabetic (NOD), and C57BL/6 (B6). Studies employing alamethicin and inhibitors were able to again localize the heightened ROS production in ALR.mt^NOD to complex III and identified complex I as the site of elevated ROS production from NOD and B6 mitochondria. Using submitochondrial particles, we confirmed that in the context of the NOD or B6 nuclear genomes, mt-Nd2^c elevates complex I-specific ROS production. In all assays mitochondria from mt-Nd2^a-encoding strains exhibited low ROS production. Our data suggest that lowering overall mitochondrial ROS production is a key mechanism of disease protection provided by mt-Nd2^a.

Received for publication, October 25, 2007 , and in revised form, January 24, 2008.

^* This work was supported by grants from the Juvenile Diabetes Research Foundation and by National Institutes of Health Grant R01 DK74656. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–4.

¹ To whom correspondence should be addressed: 1600 S. W. Archer Rd., P. O. Box 100275, Gainesville, FL 32610-0275. E-mail: clayton.mathews{at}pathology.ufl.edu.

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