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J. Biol. Chem., Vol. 280, Issue 17, 16559-16570, April 29, 2005

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A Mitochondrial NADH-dependent Fumarate Reductase Involved in the Production of Succinate Excreted by Procyclic Trypanosoma brucei^*

Virginie Coustou, Sébastien Besteiro, Loïc Rivière, Marc Biran¶, Nicolas Biteau, Jean-Michel Franconi¶, Michael Boshart||, Théo Baltz, and Frédéric Bringaud**

From the Laboratoire de Génomique Fonctionnelle des Trypanosomatides, UMR-5162 CNRS, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux cedex, France, ^¶Résonance Magnétique des Systèmes Biologiques, UMR-5536 CNRS, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux cedex, France, and the ^||Department Biology I, Genetics, Ludwig Maximilian University Munich, D-80638 München, Germany

Trypanosoma brucei is a parasitic protist responsible for sleeping sickness in humans. The procyclic stage of T. brucei expresses a soluble NADH-dependent fumarate reductase (FRDg) in the peroxisome-like organelles called glycosomes. This enzyme is responsible for the production of about 70% of the excreted succinate, the major end product of glucose metabolism in this form of the parasite. Here we functionally characterize a new gene encoding FRD (FRDm1) expressed in the procyclic stage. FRDm1 is a mitochondrial protein, as evidenced by immunolocalization, fractionation of digitonin-permeabilized cells, and expression of EGFP-tagged FRDm1 in the parasite. RNA interference was used to deplete FRDm1, FRDg, or both together. The analysis of the resulting mutant cell lines showed that FRDm1 is responsible for 30% of the cellular NADH-FRD activity, which solves a long standing debate regarding the existence of a mitochondrial FRD in trypanosomatids. FRDg and FRDm1 together account for the total NADH-FRD activity in procyclics, because no activity was measured in the double mutant lacking expression of both proteins. Analysis of the end products of ¹³C-enriched glucose excreted by these mutant cell lines showed that FRDm1 contributes to the production of between 14 and 44% of the succinate excreted by the wild type cells. In addition, depletion of one or both FRD enzymes results in up to 2-fold reduction of the rate of glucose consumption. We propose that FRDm1 is involved in the maintenance of the redox balance in the mitochondrion, as proposed for the ancestral soluble FRD presumably present in primitive anaerobic cells.

Received for publication, January 11, 2005 , and in revised form, February 9, 2005.

^* This work was supported by the CNRS, the Conseil Régional d'Aquitaine, the Ministère de l'Education Nationale de la Recherche et de la Technologie, and the International Scientific Cooperation Projects (INCO-DEV) Program of the European Commission. 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.

Present address: Wellcome Centre for Molecular Parasitology, Anderson College, University of Glasgow, 56 Dumbarton Road, Glasgow, G11 6NU, UK.

^** To whom correspondence should be addressed. Tel.: 33-5-57-57-46-32; Fax: 33-5-57-57-48-03; E-mail: bringaud{at}u-bordeaux2.fr.

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