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J. Biol. Chem., Vol. 278, Issue 46, 45154-45159, November 14, 2003

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Cardiac Mitochondrial NADP⁺-isocitrate Dehydrogenase Is Inactivated through 4-Hydroxynonenal Adduct Formation

AN EVENT THAT PRECEDES HYPERTROPHY DEVELOPMENT^*

Mohamed Benderdour, Guy Charron, Denis deBlois¶||, Blandine Comte, and Christine Des Rosiers**

From the Departments of Nutrition, Medicine, and ^||Pharmacology, Université de Montréal, Montréal, Québec H3C 3J7, Canada

Mitochondrial NADP⁺-isocitrate dehydrogenase activity is crucial for cardiomyocyte energy and redox status, but much remains to be learned about its role and regulation. We obtained data in spontaneously hypertensive rat hearts that indicated a partial inactivation of this enzyme before hypertrophy development. We tested the hypothesis that cardiac mitochondrial NADP⁺-isocitrate dehydrogenase is a target for modification by the lipid peroxidation product 4-hydroxynonenal, an aldehyde that reacts readily with protein sulfhydryl and amino groups. This hypothesis is supported by the following in vitro and in vivo evidence. In isolated rat heart mitochondria, enzyme inactivation occurred within a few minutes upon incubation with 4-hydroxynonenal and was paralleled by 4-hydroxynonenal/NADP⁺-isocitrate dehydrogenase adduct formation. Enzyme inactivation was prevented by the addition of its substrate isocitrate or a thiol, cysteine or glutathione, suggesting that 4-hydroxynonenal binds to a cysteine residue near the substrate's binding site. Using an immunoprecipitation approach, we demonstrated the formation of 4-hydroxynonenal/NADP⁺-isocitrate dehydrogenase adducts in the heart and their increased level (210%) in 7-week-old spontaneously hypertensive rats compared with control Wistar Kyoto rats. To the best of our knowledge, this is the first study to demonstrate that mitochondrial NADP⁺-isocitrate dehydrogenase is a target for inactivation by 4-hydroxynonenal binding. Furthermore, the pathophysiological significance of our finding is supported by in vivo evidence. Taken altogether, our results have implications that extend beyond mitochondrial NADP⁺-isocitrate dehydrogenase. Indeed, they emphasize the implication of post-translational modifications of mitochondrial metabolic enzymes by 4-hydroxynonenal in the early oxidative stress-related pathophysiological events linked to cardiac hypertrophy development.

Received for publication, June 13, 2003 , and in revised form, September 4, 2003.

^* This study was supported by Canadian Institutes of Health Research Grant #10816 (to C. D. R.). Part of this work was published as an abstract at the 9th Oxygen Society Meeting, Nov. 20–24, 2002 and at the European Section of the Society for Free Radical Research Meeting, June 26–29, 2003. 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.

^¶ Scholar of the Fonds de la Recherche en Santé du Québec.

^** To whom correspondence should be addressed: Laboratoire du Métabolisme Intermédiaire, Centre Hospitalier de l'Université de Montréal-Hôpital Notre Dame (Y-3616), 1560 rue Sherbrooke Est, Montréal, QC H2L 4M1, Canada. Tel.: 514-890-8000 (ext. 27477), Fax: 514-412-7661; E-mail: christine.des.rosiers{at}umontreal.ca.

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