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Dissecting the mitochondrial oxidative defense of Trypanosoma cruzi

Grant number: 10/02443-9
Support type:Scholarships abroad - Research
Effective date (Start): July 08, 2010
Effective date (End): October 22, 2010
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal researcher:Fernanda Ramos Gadelha
Grantee:Fernanda Ramos Gadelha
Host: Shane Wilkinson
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Research place: Queen Mary University of London, England  

Abstract

The requirement for new treatments targeting Trypanosoma cruzi, the causative agent of Chagas disease, is urgently needed. One potential Achilles? heel is the systems it employs to detoxify reactive oxygen species. For peroxide metabolism, a series of enzymatic pathways dependent on the trypanosome specific thiol trypanothione have been reported. However, although a mitochondrial antioxidant tryparedoxin peroxidase from T. cruzi has been characterized, how reducing equivalents are transferred to this enzyme has not been elucidated. A tryparedoxin (TcTPNII) with identity to a cytosolic tryparedoxin (TcTPNI) has been identified from the T. cruzi genome database but its function has yet to be examined. Bioinformatic analysis indicates it contains a hydrophobic carboxyl-terminal extension that may anchor it to the mitochondrial membrane. We have demonstrated that cells that overexpressed mitochondrial tryparedoxin peroxidase (MPx) have higher respiratory rates, lower respiratory control (RC), and similar mitochondrial membrane potential than pTEx (control) and cytosolic tryparedoxin peroxidase overexpressing cells. One hypothesis that we came up with to explain these results was that in MPx, TcTPNII would also be overexpressed creating another path for the protons to re-enter the matrix, leading to the lower RC and higher respiratory rates observed. The aim of this project is to biochemically characterize and functionally dissect the role played by this protein in the parasite and confirm its sub-cellular location. This will provide a framework that will allow us to determine whether TcTPNII can be exploited in terms of novel chemotherapies. (AU)

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