Mitochondrial complex III defects contribute to inefficient respiration and ATP synthesis in the myocardium of Trypanosoma cruzi-infected mice.
In this study, we conducted a thorough analysis of mitochondrial bioenergetic function as well as the biochemical and molecular factors that are deregulated and contribute to compromised adenosine triphosphate (ATP) production in the myocardium during Trypanosoma cruzi infection. We show that ADP-stimulated state 3 respiration and ATP synthesis supported by pyruvate/malate (provides electrons to complex I) and succinate (provides electrons to complex II) substrates were significantly decreased in left ventricular tissue and isolated cardiac mitochondria of infected mice. The decreased mitochondrial ATP synthesis in infected murine hearts was not a result of uncoupling between the electron-transport chain and oxidative phosphorylation and decreased availability of the intermediary metabolites (e.g., NADH). The observed decline in the activities of complex-I, -IV, and -V was not physiologically relevant and did not contribute to compromised respiration and ATP synthesis in infected myocardium. Instead, complex III activity was decreased above the threshold level and contributed to respiratory-chain inefficiency and the resulting decline in mitochondrial ATP synthesis in infected myocardium. The loss in complex III activity occurred as a consequence of cytochrome b depletion. Treatment of infected mice with phenyl-alpha-tert-butyl nitrone (PBN, antioxidant) was beneficial in preserving the mtDNA-encoded cytochrome b expression, and subsequently resulted in improved complex III activity, mitochondrial respiration, and ATP production in infected myocardium. Overall, we provide novel data on the mechanism(s) involved in cardiac bioenergetic inefficiency during T. cruzi infection.
Wen
Jian-Jun
JJ
Department of Microbiology & Immunology, The Center for Biodefense & Emerging Infectious Diseases, and The Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas 77555-1070, USA.
Garg
Nisha Jain
NJ
D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D014355:Chagas Disease / Q000201:enzymology / Q000378:metabolism*; D045303:Cytochromes b / Q000235:genetics / Q000378:metabolism; D014450:Electron Transport Complex III / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009206:Myocardium / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D014349:Trypanosoma cruzi / Q000302:isolation & purification*
D000255:Adenosine Triphosphate; D045303:Cytochromes b; D014450:Electron Transport Complex III; D010100:Oxygen