Trypanosoma cruzi undergo PCD (programmed cell death) under appropriate stimuli, the mechanisms of which remain to be established. In the present study, we show that stimulation of PCD in T. cruzi epimastigotes by FHS (fresh human serum) results in rapid (<1 h) externalization of phosphatidylserine and depletion of the low molecular mass thiols dihydrotrypanothione and glutathione. Concomitantly, enhanced generation of oxidants was established by EPR and immuno-spin trapping of radicals using DMPO (5,5-dimethylpyrroline-N-oxide) and augmentation of the glucose flux through the pentose phosphate pathway. In the early period (<20 min), changes in mitochondrial membrane potential and inhibition of respiration, probably due to the impairment of ADP/ATP exchange with the cytosol, were observed, conditions that favour the generation of O2•−. Accelerated rates of mitochondrial O2•− production were detected by the inactivation of the redox-sensitive mitochondrial aconitase and by oxidation of a mitochondrial-targeted probe (MitoSOX). Importantly, parasites overexpressing mitochondrial FeSOD (iron superoxide dismutase) were more resistant to the PCD stimulus, unambiguously indicating the participation of mitochondrial O2•− in the signalling process. In summary, FHS-induced PCD in T. cruzi involves mitochondrial dysfunction that causes enhanced O2•− formation, which leads to cellular oxidative stress conditions that trigger the initiation of PCD cascades; moreover, overexpression of mitochondrial FeSOD, which is also observed during metacyclogenesis, resulted in cytoprotective effects.
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Research Article|
March 26 2007
Mitochondrial superoxide radicals mediate programmed cell death in Trypanosoma cruzi: cytoprotective action of mitochondrial iron superoxide dismutase overexpression
Lucía Piacenza;
Lucía Piacenza
*Departamento de Bioquímica, Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
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Florencia Irigoín;
Florencia Irigoín
†Departamento de Histología y Embriología, Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
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María Noel Alvarez;
María Noel Alvarez
*Departamento de Bioquímica, Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
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Gonzalo Peluffo;
Gonzalo Peluffo
*Departamento de Bioquímica, Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
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Martin C. Taylor;
Martin C. Taylor
‡Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, U.K.
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John M. Kelly;
John M. Kelly
‡Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, U.K.
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Shane R. Wilkinson;
Shane R. Wilkinson
‡Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, U.K.
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Rafael Radi
Rafael Radi
1
*Departamento de Bioquímica, Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
1To whom correspondence should be addressed (email rradi@fmed.edu.uy).
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Publisher: Portland Press Ltd
Received:
August 22 2006
Revision Received:
December 05 2006
Accepted:
December 14 2006
Accepted Manuscript online:
December 14 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2007
Biochem J (2007) 403 (2): 323–334.
Article history
Received:
August 22 2006
Revision Received:
December 05 2006
Accepted:
December 14 2006
Accepted Manuscript online:
December 14 2006
Citation
Lucía Piacenza, Florencia Irigoín, María Noel Alvarez, Gonzalo Peluffo, Martin C. Taylor, John M. Kelly, Shane R. Wilkinson, Rafael Radi; Mitochondrial superoxide radicals mediate programmed cell death in Trypanosoma cruzi: cytoprotective action of mitochondrial iron superoxide dismutase overexpression. Biochem J 15 April 2007; 403 (2): 323–334. doi: https://doi.org/10.1042/BJ20061281
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