title: Impaired mitochondrial respiratory chain and bioenergetics during chagasic cardiomyopathy development.
abstract: In this study, we evaluated the activities of respiratory chain complexes and oxidative phosphorylation (OXPHOS) capacity of the heart to gain insights into the pathological significance of mitochondrial dysfunction in chagasic cardiomyopathy (CCM). In a murine model of Trypanosoma cruzi infection, biochemical and histochemical analysis of the cardiac mitochondria revealed deficiency of the respiratory chain complexes (CI-CV) in infected mice; the inhibition of CI activity was more pronounced in the acute infection phase, CIII was constitutively repressed throughout the infection and disease phase, and the CV defects appeared in chronic phase only. A substantial decline in cardiac mtDNA content (54-60%) and mitochondria-encoded transcripts (50-65%) with disease development indicated that the alterations in mtDNA contribute to the quantitative deficiencies in respiratory chain activity in chagasic hearts. The observations of a selective inhibition of redox-sensitive CI and CIII complexes that are also the site of free radical generation in mitochondria, and the decline in cardiac mtDNA content in infected mice, all support the free radical hypothesis of mitochondria dysfunction in CCM. Consequently, OXPHOS-mediated ATP synthesis capacity of the cardiac mitochondria in infected mice was substantially reduced (37-50%), suggesting an energy homeostasis in the affected tissue.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.
authors.forename: Galina
authors.initials: G
authors.lastname: Vyatkina
authors.forename: Vandanajay
authors.initials: V
authors.lastname: Bhatia
authors.forename: Arpad
authors.initials: A
authors.lastname: Gerstner
authors.forename: John
authors.initials: J
authors.lastname: Papaconstantinou
authors.forename: Nisha
authors.initials: N
authors.lastname: Garg
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002598:Chagas Cardiomyopathy / Q000150:complications / Q000201:enzymology*; D018450:Disease Progression; D042967:Electron Transport Complex I / Q000378:metabolism; D014450:Electron Transport Complex III / Q000378:metabolism; D004734:Energy Metabolism; D005609:Free Radicals; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008928:Mitochondria / Q000201:enzymology*; D028361:Mitochondrial Diseases / Q000209:etiology / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: D005609:Free Radicals; D010088:Oxidoreductases; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III