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J Bioenerg Biomembr. 2008 Dec;40(6):587-98. doi: 10.1007/s10863-008-9184-4. Epub 2008 Nov 14.

Mitochondrial generation of reactive oxygen species is enhanced at the Q(o) site of the complex III in the myocardium of Trypanosoma cruzi-infected mice: beneficial effects of an antioxidant.

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Departments of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-1070, USA.


In this study, we have characterized the cellular source and mechanism for the enhanced generation of reactive oxygen species (ROS) in the myocardium during Trypanosoma cruzi infection. Cardiac mitochondria of infected mice, as compared to normal controls, exhibited 63.3% and 30.8% increase in ROS-specific fluorescence of dihydroethidium (detects O(2) (*-)) and amplex red (detects H(2)O(2)), respectively. This increase in ROS level in cardiac mitochondria of infected mice was associated with a 59% and 114% increase in the rate of glutamate/malate- (complex I substrates) and succinate- (complex II substrate) supported ROS release, respectively, and up to a 74.9% increase in the rate of electron leakage from the respiratory chain when compared to normal controls. Inhibition studies with normal cardiac mitochondria showed that rotenone induced ROS generation at the Q(Nf)-ubisemiquinone site in complex I. In complex III, myxothiazol induced ROS generation from a site located at the Q(o) center that was different from the Q(i) center of O(2) (*-) generation by antimycin. In cardiac mitochondria of infected mice, the rate of electron leakage at complex I during forward (complex I-to-complex III) and reverse (complex II-to-complex I) electron flow was not enhanced, and complex I was not the main site of increased ROS production in infected myocardium. Instead, defects of complex III proximal to the Q(o) site resulted in enhanced electron leakage and ROS formation in cardiac mitochondria of infected mice. Treatment of infected mice with phenyl-alpha-tert-butyl-nitrone (PBN) improved the respiratory chain function, and, subsequently, decreased the extent of electron leakage and ROS release. In conclusion, we show that impairment of the Q(o) site of complex III resulted in increased electron leakage and O(2) (*-) formation in infected myocardium, and was controlled by PBN.

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