Trypanosoma cruzi response to sterol biosynthesis inhibitors: morphophysiological alterations leading to cell death.

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 he...

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Autores principales:	Rafael Luis Kessler, Maurilio José Soares, Christian Macagnan Probst, Marco Aurélio Krieger
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2b01eedac0dc4244a50b6389ca1fe82f
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spelling	oai:doaj.org-article:2b01eedac0dc4244a50b6389ca1fe82f2021-11-18T07:59:08ZTrypanosoma cruzi response to sterol biosynthesis inhibitors: morphophysiological alterations leading to cell death.1932-620310.1371/journal.pone.0055497https://doaj.org/article/2b01eedac0dc4244a50b6389ca1fe82f2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23383204/?tool=EBIhttps://doaj.org/toc/1932-6203The 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% (EC(50)/72 h) or killing all cells within 24 hours (EC(100)/24 h). Incubation with inhibitors at the EC(50)/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 EC(50)/72 h. By contrast, treatment with SBIs at the EC(100)/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.Rafael Luis KesslerMaurilio José SoaresChristian Macagnan ProbstMarco Aurélio KriegerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 1, p e55497 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rafael Luis Kessler Maurilio José Soares Christian Macagnan Probst Marco Aurélio Krieger Trypanosoma cruzi response to sterol biosynthesis inhibitors: morphophysiological alterations leading to cell death.
description	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% (EC(50)/72 h) or killing all cells within 24 hours (EC(100)/24 h). Incubation with inhibitors at the EC(50)/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 EC(50)/72 h. By contrast, treatment with SBIs at the EC(100)/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.
format	article
author	Rafael Luis Kessler Maurilio José Soares Christian Macagnan Probst Marco Aurélio Krieger
author_facet	Rafael Luis Kessler Maurilio José Soares Christian Macagnan Probst Marco Aurélio Krieger
author_sort	Rafael Luis Kessler
title	Trypanosoma cruzi response to sterol biosynthesis inhibitors: morphophysiological alterations leading to cell death.
title_short	Trypanosoma cruzi response to sterol biosynthesis inhibitors: morphophysiological alterations leading to cell death.
title_full	Trypanosoma cruzi response to sterol biosynthesis inhibitors: morphophysiological alterations leading to cell death.
title_fullStr	Trypanosoma cruzi response to sterol biosynthesis inhibitors: morphophysiological alterations leading to cell death.
title_full_unstemmed	Trypanosoma cruzi response to sterol biosynthesis inhibitors: morphophysiological alterations leading to cell death.
title_sort	trypanosoma cruzi response to sterol biosynthesis inhibitors: morphophysiological alterations leading to cell death.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/2b01eedac0dc4244a50b6389ca1fe82f
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Trypanosoma cruzi response to sterol biosynthesis inhibitors: morphophysiological alterations leading to cell death.

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