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J. Biol. Chem., Vol. 282, Issue 8, 5171-5179, February 23, 2007

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Nuclear and Mitochondrial Interaction Involving mt-Nd2 Leads to Increased Mitochondrial Reactive Oxygen Species Production^*

Aaron M. Gusdon, Tatyana V. Votyakova, Ian J. Reynolds¹, and Clayton E. Mathews²

From the Department of Pediatrics, the University of Pittsburgh School of Medicine and The Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213 and the Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

NADH dehydrogenase subunit 2, encoded by the mtDNA, has been associated with resistance to autoimmune type I diabetes (T1D) in a case control study. Recently, we confirmed a role for the mouse ortholog of the protective allele (mt-Nd2^a) in resistance to T1D using genetic analysis of outcrosses between T1D-resistant ALR and T1D-susceptible NOD mice. We sought to determine the mechanism of disease protection by elucidating whether mt-Nd2^a affects basal mitochondrial function or mitochondrial function in the presence of oxidative stress. Two lines of reciprocal conplastic mouse strains were generated: one with ALR nuclear DNA and NOD mtDNA (ALR.mt^NOD) and the reciprocal with NOD nuclear DNA and ALR mtDNA (NOD.mt^ALR). Basal mitochondrial respiration, transmembrane potential, and electron transport system enzymatic activities showed no difference among the strains. However, ALR.mt^NOD mitochondria supported by either complex I or complex II substrates produced significantly more reactive oxygen species when compared with both parental strains, NOD.mt^ALR or C57BL/6 controls. Nitric oxide inhibited respiration to a similar extent for mitochondria from the five strains due to competitive antagonism with molecular oxygen at complex IV. Superoxide and hydrogen peroxide generated by xanthine oxidase did not significantly decrease complex I function. The protein nitrating agents peroxynitrite or nitrogen dioxide radicals significantly decreased complex I function but with no significant difference among the five strains. In summary, mt-Nd2^a does not confer elevated resistance to oxidative stress; however, it plays a critical role in the control of the mitochondrial reactive oxygen species production.

Received for publication, October 4, 2006 , and in revised form, November 28, 2006.

^* This work was supported by grants from the Juvenile Diabetes Association (to C. E. M.) and by Grants AI056374 (to C. E. M.), DK074656 (to C. E. M.), and AG20899 (to I. J. R.) from the National Institutes of Health. 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 Table and Figs. A–D.

¹ Present address: Merck Research Laboratories, Merck, WP42-229, 770 Sumneytown Pike, P. O. Box 4, West Point, PA 19486-0004.

² To whom correspondence should be addressed: Dept. of Pediatrics, Diabetes Institute, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 3460 5th Ave., Rangos Research Center, Pittsburgh, PA 15213. Tel.: 412-692-8574; Fax: 412-692-8131; E-mail: cem65{at}pitt.edu.

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