Figure 6. Proposed model of ZIPCO's role in iron homeostasis during P. berghei liver-stage development.

Based on our analyses of the sizes of WT-F and ZIPCO-F liver stages in normal media and media supplemented with or depleted of iron, together with the increased sensitivity of ZIPCO-F parasites to the iron chelator (DFO), we propose that WT-F liver stages (black circle) possess at least two iron transporters, ZIPCO shown as green cylinder and a second shown in blue. WT-F parasites grown in DMEM obtain sufficient amounts of iron for normal development. ZIPCO-F mutant parasites (shown in red) lack the iron transport activity of ZIPCO and use the second transporter to obtain some, but insufficient amounts, of iron for normal growth. Supplementing the media with ferric ammonium citrate (FAC) does not increase the growth of WT-F parasites since they obtain sufficient iron. On the contrary, extra iron in the media stimulates the growth of ZIPCO-F parasites. The presence of DFO, an iron chelator, removes iron and thereby blocks the growth of both WT-F and ZIPCO-F parasites. The effect of DFO is indeed due to the removal of iron since DFO + FAC results in normal growth of WT-F parasites and improved growth of ZIPCO-F mutants.