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MBC in Press, published online ahead of print December 29, 2003
Mol. Biol. Cell 10.1091/mbc.E03-10-0720

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Submitted on October 7, 2003
Revised on November 4, 2003
Accepted on November 4, 2003

Mitochondrial Localization of the Mevalonate Pathway Enzyme 3-Hydroxy-3-methyl-glutaryl-CoA reductase in the Trypanosomatidae

Javier Peña-Diaz1, Andrea Montalvetti1, Carmen-Lisset Flores2, Aurora Constán1, Ramon Hurtado-Guerrero1, Wanderley De Souza3, Carlos Gancedo2, Luis M. Ruiz-Perez1, and Dolores Gonzalez-Pacanowska1*

1 Instituto de Parasitología y Biomedicina "López-Neyra", Consejo Superior de Investigaciones Científicas, C/ Ventanilla 11, 18001 Granada
2 Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas, C/ Arturo Duperier 4, 28029 Madrid, Spain
3 Instituto de Biofísica Carlos Chagas Filho, Universidad Federal do Rio de Janeiro, Brasil

* Corresponding author. E-mail address: dgonzalez{at}ipb.csic.es.

3-Hydroxy-3-methyl-glutaryl-CoA reductase (HMGR) is a key enzyme in the sterol biosynthesis pathway but its subcellular distribution in the Trypanosomatidae family is somewhat controversial. Trypanosoma cruzi and Leishmania HMGRs are closely related in their catalytic domains to bacterial and eukaryotic enzymes described but lack an amino-terminal domain responsible for the attachment to the endoplasmic reticulum. In the present study digitonin-titration experiments together with immunoelectron microscopy were used to establish the intracellular localization of HMGR in these pathogens. RESULTS obtained with wild-type cells and transfectants overexpressing the enzyme established that HMGR in both T. cruzi and Leishmania major is localized primarily in the mitochondrion and that elimination of the mitochondrial targeting sequence in Leishmania leads to protein accumulation in the cytosolic compartment. Furthermore, TcHMGR is efficiently targeted to the mitochondrion in yeast cells. Thus, when the gene encoding T. cruzi HMGR was expressed in a hmg1 hmg2 mutant of S. cerevisiae, the mevalonate auxotrophy of mutant cells was relieved and immunoelectron analysis showed that the parasite enzyme exhibits a mitochondrial localization suggesting a conservation between the targeting signals of both organisms.




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