In this study, we investigated the mechanism(s) of mitochondrial functional decline in acute
Chagas' disease. Our data show a substantial decline in respiratory complex activities (39 to 58%) and
ATP (38%) content in Trypanosoma cruzi-infected murine hearts compared with normal controls. These metabolic alterations were associated with an approximately fivefold increase in mitochondrial
reactive oxygen species production rate, substantial oxidative insult of mitochondrial membranes and respiratory complex subunits, and >60% inhibition of
mtDNA-encoded transcripts for respiratory complex subunits in infected myocardium. The
antioxidant phenyl-alpha-tert-butyl nitrone (PBN) arrested the oxidative damage-mediated loss in mitochondrial membrane integrity, preserved redox potential-coupled mitochondrial gene expression, and improved respiratory complex activities (47 to 95% increase) and cardiac
ATP level (>or=40% increase) in infected myocardium. Importantly, PBN resulted twofold decline in mitochondrial
reactive oxygen species production rate in infected myocardium. Taken together, our data demonstrate the pathological significance of oxidative stress in metabolic decay and energy homeostasis in acute chagasic
myocarditis and further suggest that oxidative injuries affecting mitochondrial integrity-dependent expression and activity of the respiratory complexes initiate a feedback cycle of electron transport chain inefficiency, increased
reactive oxygen species production, and energy homeostasis in acute chagasic hearts. PBN and other mitochondria-targeted
antioxidants may be useful in altering mitochondrial decay and oxidative pathology in
Chagas' disease.