Phenyl-alpha-tert-butyl nitrone reverses mitochondrial decay in acute Chagas' disease.
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.
Wen
Jian-Jun
JJ
Department of Microbiology, 3.142C Medical Research Building, University of Texas Medical Branch, 301 University Blvd., Galveston TX 77555, USA.
Bhatia
Vandanajay
V
Popov
Vsevolod L
VL
Garg
Nisha Jain
NJ
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002460:Cell Line; D014355:Chagas Disease / Q000188:drug therapy*; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004579:Electron Transport / Q000187:drug effects; D006321:Heart / Q000469:parasitology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000469:parasitology / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*
D000975:Antioxidants; D003497:Cyclic N-Oxides; C029217:phenyl-N-tert-butylnitrone