Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/16039
Title: Trypanosoma cruzi response to Sterol Biosynthesis Inhibitors: morphophysiological alterations leading to cell death
Authors: Kessler, Rafael Luis
Soares, Maurilio José
Probst, Christian Macagnan
Krieger, Marco Aurélio
Affilliation: Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil.
Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil.
Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil.
Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil.
Abstract: The protozoan parasite Trypanosoma cruzi displays similarities to fungi in terms of its sterol lipid biosynthesis, as ergosterol and other 24-alkylated sterols are its principal endogenous sterols. The sterol pathway is thus a potential drug target for the treatment of Chagas disease. We describe here a comparative study of the growth inhibition, ultrastructural and physiological changes leading to the death of T. cruzi cells following treatment with the sterol biosynthesis inhibitors (SBIs) ketoconazole and lovastatin. We first calculated the drug concentration inhibiting epimastigote growth by 50% (EC50/72 h) or killing all cells within 24 hours (EC100/24 h). Incubation with inhibitors at the EC50/72 h resulted in interesting morphological changes: intense proliferation of the inner mitochondrial membrane, which was corroborated by flow cytometry and confocal microscopy of the parasites stained with rhodamine 123, and strong swelling of the reservosomes, which was confirmed by acridine orange staining. These changes to the mitochondria and reservosomes may reflect the involvement of these organelles in ergosterol biosynthesis or the progressive autophagic process culminating in cell lysis after 6 to 7 days of treatment with SBIs at the EC50/72 h. By contrast, treatment with SBIs at the EC100/24 h resulted in rapid cell death with a necrotic phenotype: time-dependent cytosolic calcium overload, mitochondrial depolarization and reservosome membrane permeabilization (RMP), culminating in cell lysis after a few hours of drug exposure. We provide the first demonstration that RMP constitutes the “point of no return” in the cell death cascade, and propose a model for the necrotic cell death of T. cruzi. Thus, SBIs trigger cell death by different mechanisms, depending on the dose used, in T. cruzi. These findings shed new light on ergosterol biosynthesis and the mechanisms of programmed cell death in this ancient protozoan parasite.
Keywords: Trypanosoma cruzi
Sterol Biosynthesis Inhibitors
DeCS: Esteróis
Cetoconazol
Inibidores de 14-alfa Desmetilase
Lovastatina
Inibidores de Hidroximetilglutaril-CoA Redutases
Issue Date: 2013
Publisher: Iratxe Puebla
Citation: KESSLER, Rafael Luis et al. Trypanosoma cruzi response to Sterol Biosynthesis Inhibitors: morphophysiological alterations leading to cell death. PLoS ONE, v. 8, n. 1, p. 1-16, 2013.
ISSN: 1932-6203
Copyright: open access
Appears in Collections:PR - ICC - Artigos de Periódicos

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