Thiol redox control in the single mitochondrion of trypanosomes

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Trypanosomatids, to which belong the causative agents of several tropical diseases, have an unusual trypanothione-based thiol redox metabolism. The parasite-specific metabolite is synthesized from spermidine and two molecules of glutathione and kept reduced by the flavoenzyme trypanothione reductase. All enzymes involved in the biosynthesis as well as trypanothione reductase exclusively occur in the cytosol. Here, trypanothione reduces glutathione disulfide by direct thiol/disulfide exchange and provides the reducing equivalents for various redox proteins such as tryparedoxin, thioredoxin and glutaredoxin. For none of the trypanosomatid organism, the low molecular mass thiol(s) in any subcellular organelle has/have been identified. Aim of this project is to elucidate if glutathione and/or trypanothione occur in the stage-dependent regulated single mitochondrion of Trypanosoma brucei, how the thiols are transferred into the organelle and how the redox balance of the cytosolic and mitochondrial thiol pools are affected when the parasites are oxidatively stressed. The second approach deals with the physiological role of a probably essential mitochondrial thioredoxin-type protein which does not have any counterpart outside the trypanosomatids. These studies will comprise the structural and functional analysis of the recombinant protein as well as the generation and characterization of conditional knockout parasites. The planned work should provide us with a comprehensive insight into the thiol metabolism of the singular mitochondrion of these parasites and unravel if the novel thioredoxin is the missing link between the low molecular mass thiols and the mitochondrial thiol peroxidases.