FIG. 3.

Putative roles of the glutaredoxins in the thiol and iron metabolism of African trypanosomes. African trypanosomes obtain iron by the uptake of iron-loaded transferrin (Tf-Fe) from the host blood via receptor-mediated (Tf-R) endocytosis. In the late endosome, Fe is released and exported into the cytosol. Here it circulates in complex with low molecular mass ligands (Fe–L) and can be translocated into the mitochondrial matrix. As shown for yeast and mammalian cells as well as partially for trypanosomes, the mitochondrion is the primary site for the biosynthesis of ISC that requires two specialized machineries. The mitochondrial Iron Sulfur Cluster Biogenesis (mISC-B) system synthesizes the ISC from iron and cysteine (as sulfur donor), and the Iron Sulfur Cluster Assembly (mISC-A) system then transfers the pre-formed ISC from scaffold proteins to acceptor iron sulfur proteins (ISP). T. brucei 1-C-Grx1 is an indispensable (iron sulfur) protein, probably participating in the mISC-A system. The parasite 1-C-Grx2 is a low abundant and functionally nonredundant orthologue of 1-C-Grx1. How ISC is exported from the mitochondrion is not yet known. In the cytosol, 1-C-Grx3 and 2-C-Grx1 may be part of the cytosolic iron assembly (CIA) machinery that transforms apo-iron sulfur proteins (apo-ISP) into the respective holo-proteins (holo-ISP). Alternatively, ISC formation on 2-C-Grx1 may result in an inactive form that, in the presence of high levels of reactive oxygen species (ROS), may be converted again in the free protein (for further abbreviations, see legend of Fig. 1). 2-C-Grx2 in the—intermembrane space (IMS) and/or matrix of the—mitochondrion plays probably a crucial role for the reduction of protein disulfides and/or glutathionylated proteins (Pr-S-SG) produced by reactive oxygen species (ROS) originating from the respiratory chain and cytochrome c (cyt c) activity present only in the insect stage of the parasite. The scheme is based on data from reference 55 and citations therein.