Mitochondrial generation of reactive oxygen species is enhanced at the Qo site of the complex III in the myocardium of Trypanosoma cruzi-infected mice: Beneficial effects of an antioxidant

Jian Jun Wen, Nisha Garg

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38 Citations (Scopus)

Abstract

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 O2 •-) and amplex red (detects H2O2), 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 Qo center that was different from the Qi center of O2 •- 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 Qo site resulted in enhanced electron leakage and ROS formation in cardiac mitochondria of infected mice. Treatment of infected mice with phenyl-α-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 Qo site of complex III resulted in increased electron leakage and O2 •- formation in infected myocardium, and was controlled by PBN.

Original languageEnglish (US)
Pages (from-to)587-598
Number of pages12
JournalJournal of Bioenergetics and Biomembranes
Volume40
Issue number6
DOIs
StatePublished - Dec 2008

Fingerprint

Electron Transport Complex III
Trypanosoma cruzi
Reactive Oxygen Species
Myocardium
Antioxidants
Electrons
Mitochondria
coenzyme Q10
Electron Transport
Qi
Rotenone
Succinic Acid
Glutamic Acid
Fluorescence

Keywords

  • Chagas disease
  • Electron transport chain
  • Mitochondria
  • Myocardium
  • Reactive oxygen species
  • Site of ROS production

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

Cite this

@article{9cbf7953173045db9c638380ff62ba6b,
title = "Mitochondrial generation of reactive oxygen species is enhanced at the Qo site of the complex III in the myocardium of Trypanosoma cruzi-infected mice: Beneficial effects of an antioxidant",
abstract = "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 O2 •-) and amplex red (detects H2O2), 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 Qo center that was different from the Qi center of O2 •- 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 Qo site resulted in enhanced electron leakage and ROS formation in cardiac mitochondria of infected mice. Treatment of infected mice with phenyl-α-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 Qo site of complex III resulted in increased electron leakage and O2 •- formation in infected myocardium, and was controlled by PBN.",
keywords = "Chagas disease, Electron transport chain, Mitochondria, Myocardium, Reactive oxygen species, Site of ROS production",
author = "Wen, {Jian Jun} and Nisha Garg",
year = "2008",
month = "12",
doi = "10.1007/s10863-008-9184-4",
language = "English (US)",
volume = "40",
pages = "587--598",
journal = "Journal of Bioenergetics and Biomembranes",
issn = "0145-479X",
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TY - JOUR

T1 - Mitochondrial generation of reactive oxygen species is enhanced at the Qo site of the complex III in the myocardium of Trypanosoma cruzi-infected mice

T2 - Beneficial effects of an antioxidant

AU - Wen, Jian Jun

AU - Garg, Nisha

PY - 2008/12

Y1 - 2008/12

N2 - 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 O2 •-) and amplex red (detects H2O2), 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 Qo center that was different from the Qi center of O2 •- 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 Qo site resulted in enhanced electron leakage and ROS formation in cardiac mitochondria of infected mice. Treatment of infected mice with phenyl-α-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 Qo site of complex III resulted in increased electron leakage and O2 •- formation in infected myocardium, and was controlled by PBN.

AB - 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 O2 •-) and amplex red (detects H2O2), 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 Qo center that was different from the Qi center of O2 •- 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 Qo site resulted in enhanced electron leakage and ROS formation in cardiac mitochondria of infected mice. Treatment of infected mice with phenyl-α-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 Qo site of complex III resulted in increased electron leakage and O2 •- formation in infected myocardium, and was controlled by PBN.

KW - Chagas disease

KW - Electron transport chain

KW - Mitochondria

KW - Myocardium

KW - Reactive oxygen species

KW - Site of ROS production

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