期刊
BIOCHEMICAL JOURNAL
卷 403, 期 -, 页码 323-334出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20061281
关键词
free radicals; mitochondrial superoxide dismutase; programmed cell death (PCD); reactive oxygen species (ROS); Trypanosoma cruzi
资金
- Wellcome Trust Funding Source: Medline
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 O-2(center dot-). Accelerated rates of mitochondrial O-2(center dot-) 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 O-2(center dot-) in the signalling process. In summary, FHS-induced PCD in T cruzi involves mitochondrial dysfunction that causes enhanced O-2(center dot-) 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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