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J. Biol. Chem., Vol. 283, Issue 36, 24406-24411, September 5, 2008

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Localization of PTP-1B, SHP-2, and Src Exclusively in Rat Brain Mitochondria and Functional Consequences^*

Amal Arachiche¹, Olivier Augereau², Marion Decossas, Claire Pertuiset, Etienne Gontier, Thierry Letellier, and Jeanne Dachary-Prigent³

From the INSERM-U688 Physiopathologie Mitochondriale and the Service Commun Microscopie, Pôle Microscopie Electronique, University Victor Ségalen-Bordeaux 2, 146 rue Léo Saignat, F-33076 Bordeaux-Cedex, France

An immunodetection study of protein tyrosine phosphatase 1B (PTP-1B), SHP-2, and Src in isolated mitochondria from different rat tissues (brain, muscle, heart, liver, and kidney) revealed their exclusive localization in the brain. Given this result, we sought whether mitochondria respond to ATP and to the general tyrosine phosphatase inhibitor orthovanadate and found little or no change in the tyrosine phosphorylation profile of mitochondria from muscle, heart, liver, and kidney. In contrast, ATP induced an enhancement in the tyrosine-phosphorylated protein profile of brain mitochondria, which was further greatly enhanced with orthovanadate and which disappeared when Src was inhibited with two inhibitors: PP2 and PP1. Importantly, we found that in brain mitochondria, ATP addition induced Src autophosphorylation at Tyr-416 in its catalytic site, leading to its activation, whereas the regulatory Tyr-527 site remained unphosphorylated. Functional implications were addressed by measurements of the enzymatic activity of each of the oxidative phosphorylation complexes in brain mitochondria in the presence of ATP. We found an increase in complex I, III, and IV activity and a decrease in complex V activity, partially reversed by Src inhibition, demonstrating that the complexes are Src substrates. These results complemented and reinforced our initial study showing that respiration of brain mitochondria was partially dependent on tyrosine phosphorylation. Therefore, the present data suggest a possible control point in the regulation of respiration by tyrosine phosphorylation of the complexes mediated by Src auto-activation.

Received for publication, November 9, 2007 Accepted for publication June 24, 2008.

^* This work was supported in part by grants from INSERM, the Université Victor Segalen-Bordeaux 2, and the Fondation de France. 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.

¹ Supported by the Nouvelle Société Française d'Athérosclérose.

² Supported by the Fondation pour la Recherche Médicale.

³ To whom correspondence should be addressed. Fax: 33-5-57-57-17-03; E-mail: jeanne.dachary{at}u-bordeaux2.fr.

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