Nogueira 2017 Free Radic Biol Med

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Nogueira NP, Saraiva FMS, Oliveira MP, Mendonca APM, Inacio JDF, Almeida-Amaral EE, Menna-Barreto RF, Laranja GAT, Lopes Torres EJ, Oliveira MF, Paes MC (2017) Heme modulates Trypanosoma cruzi bioenergetics inducing mitochondrial ROS production. Free Radic Biol Med 108:183-91.

» PMID: 28363600

Nogueira NP, Saraiva FMS, Oliveira MP, Mendonca APM, Inacio JDF, Almeida-Amaral EE, Menna-Barreto RF, Laranja GAT, Lopes Torres EJ, Oliveira MF, Paes MC (2017) Free Radic Biol Med

Abstract: Trypanosoma cruzi is the causative agent of Chagas disease and has a single mitochondrion, an organelle responsible for ATP production and the main site for the formation of reactive oxygen species (ROS). T. cruzi is an obligate intracellular parasite with a complex life cycle that alternates between vertebrate and invertebrate hosts, therefore the development of survival strategies and morphogenetic adaptations to deal with the various environments is mandatory. Over the years our group has been studying the vector-parasite interactions using heme as a physiological oxidant molecule that triggered epimastigote proliferation however, the source of ROS induced by heme remained unknown. In the present study we demonstrate the involvement of heme in the parasite mitochondrial metabolism, decreasing oxygen consumption leading to increased mitochondrial ROS and membrane potential. First, we incubated epimastigotes with carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP), an uncoupler of oxidative phosphorylation, which led to decreased ROS formation and parasite proliferation, even in the presence of heme, correlating mitochondrial ROS and T. cruzi survival. This hypothesis was confirmed after the mitochondria-targeted antioxidant ((2-(2,2,6,6 Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (MitoTEMPO) decreased both heme-induced ROS and epimastigote proliferation. Furthermore, heme increased the percentage of tetramethylrhodamine methyl ester (TMRM) positive parasites tremendously-indicating the hyperpolarization and increase of potential of the mitochondrial membrane (ΔΨm). Assessing the mitochondrial functional metabolism, we observed that in comparison to untreated parasites, heme-treated epimastigotes decreased their oxygen consumption, and increased the complex II-III activity. These changes allowed the electron flow into the electron transport system, even though the complex IV (cytochrome c oxidase) activity decreased significantly, showing that heme-induced mitochondrial ROS appears to be a consequence of the enhanced mitochondrial physiological modulation. Finally, the parasites that were submitted to high concentrations of heme presented no alterations in the ultrastructure. Consequently, our results suggest that heme released by the insect vector after the blood meal, modify epimastigote mitochondrial physiology to increase ROS as a metabolic mechanism to maintain epimastigote survival and proliferation.

Keywords: Bioenergetics; Heme; Mitochondrion; Oxygen consumption; ROS; Trypanosoma cruzi Bioblast editor: Garcia-Souza LF O2k-Network Lab: BR Rio de Janeiro Paes MC, BR Rio de Janeiro Oliveira MF


Labels: MiParea: Respiration 

Stress:Oxidative stress;RONS  Organism: Protists 

Preparation: Intact organism, Permeabilized cells  Enzyme: Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase  Regulation: mt-Membrane potential  Coupling state: LEAK, ROUTINE, OXPHOS, ET  Pathway:HRR: Oxygraph-2k