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The role of the mitochondrial and glycosomal isoforms of fumarate reductase of Trypanosoma cruzi


Trypanosomatids are deficient in some of the components of the Complex I of the respiratory chain. This limits the cell ability to re-oxidize NADH to keep an adequate ratio NAD+/NADH, which in turn is critical for a normal functionality of critical metabolic pathways, such as glycolysis. Epimastigotes of Trypanosoma cruzi, the etiological agent for Chagas disease, are able to metabolize glucose during their exponential growth phase, with the production of reduced metabolites, such as succinate as end products. It was shown that succinate derives from the reduction of fumarate inside and outside the mitochondria through fumarate reductase activities. A glycosomal isoform of fumarate reductase was already shown in T. brucei, however, its presence in this organelle in T. cruzi was not shown yet. It is also not established how much the glycosome and the mitochondria contribute to the production of secreted succinate. In this context, we propose as a hypothesis that the relationship between glycosomal and mitochondrial fumarate reductase would contribute to regulate the NAD+/NADH ratio in these two organelles. In addition, given the impermeability of glycosomes to NAD+/NADH, and its permeability to fumarate/succinate, the ratio among the latter would be determinant in the "exchange of information" about the redox state in both compartments. This project aims to develop a set of exploratory experiments to have a preliminary evaluation of the sustainability of the proposed hypothesis. Prof. Wilfredo Quiñones has the expertise to obtain, purify and analyse intact glycosomes as well as their components. This expertise, combined with our experience in mitochondrial physiology, will be fundamental to obtain preliminary data to improve our knowledgment on the relationship and "metabolic communication" between the glycosome and the mitochondria in T. cruzi. Important: the present proposal is linked to (and is complemmentary to) another similar to fund the visit of Prof. Paul Michels, and is aprt of a collaboration between our group and the group of Prof. Maria Júlia Manso Alver - Instituto de QUímica - Universidade de São Paulo). (AU)

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