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J. Biol. Chem., Vol. 283, Issue 30, 20907-20913, July 25, 2008

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Identification of the Mitochondrial ND3 Subunit as a Structural Component Involved in the Active/Deactive Enzyme Transition of Respiratory Complex I^*

Alexander Galkin¹², Björn Meyer¹, Ilka Wittig, Michael Karas, Hermann Schägger, Andrei Vinogradov^¶3, and Ulrich Brandt⁴

From the Molecular Bioenergetics Group, Cluster of Excellence Frankfurt "Macromolecular complexes," Medical School, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany, the Institut für Pharmazeutische Chemie, Cluster of Excellence Frankfurt "Macromolecular complexes," Johann Wolfgang Goethe-Universität, Max-von-Laue Str.-9, D-60438 Frankfurt am Main, Germany, and the ^¶Department of Biochemistry, School of Biology, Moscow State University, Moscow 119992, Russian Federation

Mitochondrial complex I (NADH:ubiquinone oxidoreductase) undergoes reversible deactivation upon incubation at 30–37 °C. The active/deactive transition could play an important role in the regulation of complex I activity. It has been suggested recently that complex I may become modified by S-nitrosation under pathological conditions during hypoxia or when the nitric oxide:oxygen ratio increases. Apparently, a specific cysteine becomes accessible to chemical modification only in the deactive form of the enzyme. By selective fluorescence labeling and proteomic analysis, we have identified this residue as cysteine-39 of the mitochondrially encoded ND3 subunit of bovine heart mitochondria. Cysteine-39 is located in a loop connecting the first and second transmembrane helix of this highly hydrophobic subunit. We propose that this loop connects the ND3 subunit of the membrane arm with the PSST subunit of the peripheral arm of complex I, placing it in a region that is known to be critical for the catalytic mechanism of complex I. In fact, mutations in three positions of the loop were previously reported to cause Leigh syndrome with and without dystonia or progressive mitochondrial disease.

Received for publication, April 25, 2008 , and in revised form, May 23, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R03 TW07825 funded by the Fogarty International Center. This work was also supported by grants from Sonderforschungsbereich SFB628 of the Deutsche Forschungsgemeinschaft and the Cluster of Excellence EXC115 to U. B., M. K., and H. S. 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 figures and supplemental tables.

¹ Both authors contributed equally to this work.

² Supported by a scholarship from the Center for Membrane Proteomics, Frankfurt am Main. Present address: The Wolfson Institute for Biomedical Research, The Cruciform Building, University College London, Gower Street, London WC1E 6BT, UK.

³ Supported by a grant from the Russian Foundation for Fundamental Research (Grant 05-04-48809).

⁴ To whom correspondence should be addressed. Tel.: 49-69-6301-6926; Fax: 49-69-6301-6970; E-mail: brandt{at}zbc.kgu.de.

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