Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/31242
Title: Mitochondrial disfunction and ROS production are essential for anti-Trypanosoma cruzi activity of β-lapachone-derived naphthoimidazoles
Authors: Bombaça, Ana Cristina S.
Viana, Paula G.
Santos, Augusto C. C.
Silva, Thaissa L.
Rodrigues, Aline Beatriz M.
Guimarães, Ana Carolina R.
Goulart, Marilia O. F.
Silva Júnior, Eufrânio N. da
Menna-Barreto, Rubem F. S.
Affilliation: Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia. Laboratório de Pesquisa Clínica em Dermatozoonoses em Animais Domésticos. Rio de Janeiro, RJ, Brasil,
Universidade Federal de Minas Gerais. Instituto de Ciências Exatas. Departamento de Química. Belo Horizonte, MG, Brasil.
Universidade Federal de Alagoas. Instituto de Química e Biotecnologia. Maceió, AL, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ, Brasil.
Universidade Federal de Alagoas. Instituto de Química e Biotecnologia. Maceió, AL, Brasil.
Universidade Federal de Minas Gerais. Instituto de Ciências Exatas. Departamento de Química. Belo Horizonte, MG, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Abstract: Chagas disease is caused by the hemoflagellate protozoa Trypanosoma cruzi and is one of the most important neglected tropical diseases, especially in Latin American countries, where there is an association between low-income populations and mortality. The nitroderivatives used in current chemotherapy are far from ideal and present severe limitations, justifying the continuous search for alternative drugs. Since the1990s, our group has been investigating the trypanocidal activity of natural naphthoquinones and their derivatives, and three naphthoimidazoles (N1, N2 and N3) derived from β-lapachone were found to be most effective in vitro. Analysis of their mechanism of action via cellular, molecular and proteomic approaches indicates that the parasite mitochondrion contains one of the primary targets of these compounds, trypanothione synthetase (involved in trypanothione production), which is overexpressed after treatment with these compounds. Here, we further evaluated the participation of the mitochondria and reactive oxygen species (ROS) in the anti-T. cruzi action of naphthoimidazoles. Preincubation of epimastigotes and trypomastigotes with antioxidants (α-tocopherol and urate) strongly protected the parasites from the trypanocidal effect of naphthoimidazoles, decreasing the ROS levels produced and reverting the mitochondrial swelling phenotype. The addition of pro-oxidants (menadione and H2O2) before the treatment induced an increase in parasite lysis. Despite the O2 uptake and mitochondrial complex activity being strongly reduced by N1, N2 and N3, urate partially restored the mitochondrial metabolism only in N1-treated parasites. In parallel, MitoTEMPO, a mitochondrial-targeted antioxidant, protected the functionality of the mitochondria in N2- and N3-treated parasites. In addition, the trypanothione reductase activity was remarkably increased after treatment with N1 and N3, and molecular docking demonstrated that these two compounds were positioned in pockets of this enzyme. Based on our findings, the direct impairment of the mitochondrial electron transport chain by N2 and N3 led to an oxidative misbalance, which exacerbated ROS generation and led to parasite death. Although other mechanisms cannot be discounted, mainly in N1-treated parasites, further investigations are required.
Keywords: Trypanosoma cruzi
Chagas Disease
Chemotherapy
Naphthoimidazoles
Reactive oxygen species
Antioxidant defenses
keywords: Trypanosoma cruzi
Doença de Chagas
Quimioterapia
Mitocondria
Naftoimidazoles
Espécies que reagem ao oxigênio
Defesas antioxidantes
Issue Date: 2019
Publisher: Elsevier
Citation: BOMBAÇA. Ana Cristina; et al. Mitochondrial disfunction and ROS production are essential for anti-Trypanosoma cruzi activity of β-lapachone-derived naphthoimidazoles. Free Radical Biology and Medicine, v.130, p.408-418, 2019.
DOI: 10.1016/j.freeradbiomed.2018.11.012
ISSN: 0891-5849
Copyright: restricted access
Appears in Collections:IOC - Artigos de Periódicos

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