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Tomatidine promotes the inhibition of 24-alkylated sterol biosynthesis and mitochondrial dysfunction in Leishmania amazonensis promastigotes

Published online by Cambridge University Press:  01 May 2012

J. M. MEDINA ,
J. C. F. RODRIGUES ,
W. DE SOUZA ,
G. C. ATELLA  and
H. BARRABIN
J. M. MEDINA
Affiliation:
Instituto de Bioquímica Médica, UFRJ, Rio de Janeiro, Brasil
J. C. F. RODRIGUES
Affiliation:
Instituto de Biofísica Carlos Chagas Filho, UFRJ, Rio de Janeiro, Brasil Pólo Avançado de Xerém, Universidade Federal do Rio de Janeiro, Brasil
W. DE SOUZA
Affiliation:
Instituto de Biofísica Carlos Chagas Filho, UFRJ, Rio de Janeiro, Brasil
G. C. ATELLA
Affiliation:
Instituto de Bioquímica Médica, UFRJ, Rio de Janeiro, Brasil
H. BARRABIN*
Affiliation:
Instituto de Bioquímica Médica, UFRJ, Rio de Janeiro, Brasil
*
*Corresponding author: Instituto de Bioquímica Médica, Programa de Biologia Estrutural – CCS, Universidade Federal do Rio de Janeiro-UFRJ, Ilha do Fundão, 21941-590 - Rio de Janeiro, Brazil. Tel: +55 21 2590 4548. Fax: +55 21 2562 6787. E-mail: barrabin@bioqmed.ufrj.br
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Summary

Leishmaniasis is a set of clinically distinct infectious diseases caused by Leishmania, a genus of flagellated protozoan parasites, that affects ∼12 million people worldwide, with ∼2 million new infections annually. Plants are known to produce substances to defend themselves against pathogens and predators. In the genus Lycopersicon, which includes the tomato, L. esculentum, the main antimicrobial compound is the steroidal glycoalkaloid α-tomatine. The loss of the saccharide side-chain of tomatine yields the aglycone tomatidine. In the present study, we investigated the effects of tomatidine on the growth, mitochondrial membrane potential, sterol metabolism, and ultrastructure of Leishmania amazonensis promastigotes. Tomatidine (0·1 to 5 μM) inhibited parasite growth in a dose-dependent manner (IC50=124±59 nM). Transmission electron microscopy revealed lesions in the mitochondrial ultrastructure and the presence of large vacuoles and lipid storage bodies in the cytoplasm. These structural changes in the mitochondria were accompanied by an effective loss of mitochondrial membrane potential and a decrease in ATP levels. An analysis of the neutral lipid content revealed a large depletion of endogenous 24-alkylated sterols such as 24-methylene-cholesta-5, 7-dien-3β-ol (5-dehydroepisterol), with a concomitant accumulation of cholesta-8, 24-dien-3β-ol (zymosterol), which implied a perturbation in the cellular lipid content. These results are consistent with an inhibition of 24-sterol methyltransferase, an important enzyme responsible for the methylation of sterols at the 24 position, which is an essential step in the production of ergosterol and other 24-methyl sterols.

Keywords

Leishmaniatomatidinesterols24-sterol methyltransferasemitochondriatrypanosomatids
Type
Research Article
Information
Parasitology , Volume 139 , Issue 10 , September 2012 , pp. 1253 - 1265
Copyright
Copyright © Cambridge University Press 2012

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