Redox cycling in iron uptake, efflux, and trafficking

Abstract

Aerobic organisms are faced with a dilemma. Environmental iron is found primarily in the relatively inert Fe(III) form, whereas the more metabolically active ferrous form is a strong pro-oxidant. This conundrum is solved by the redox cycling of iron between Fe(III) and Fe(II) at every step in the iron metabolic pathway. As a transition metal ion, iron can be "metabolized" only by this redox cycling, which is catalyzed in aerobes by the coupled activities of ferric iron reductases (ferrireductases) and ferrous iron oxidases (ferroxidases).

FIGURE 1.

Enzootic swayback ataxia in sheep. Copper deficiency in animal husbandry, particularly in sheep, was identified in 1937 as the physiologic basis for the “swaying-back” gait phenotypic of this ataxia. The molecular link between the hypocupremia and motor dysfunction was confirmed 20 years later to be a systemic iron deficiency due in part to a decline in activity of the multicopper ferroxidase Cp. This image is from LandLearn NSW.

FIGURE 2.

Iron redox cycling in aerobic iron metabolism. A, iron uptake and efflux from the intestinal enterocyte. Fe(II) is the substrate for transport, whereas the substrate for input and output from this metabolic pathway is Fe(III). B, Fe(II) is both the input and output substrate from Ft redox cycling; Fe(III) is the metabolic intermediate in this pathway. C, iron uptake at the fungal PM inverts the Ft cycle in that Fe(III) is the input and output substrate with Fe(II) as the intermediate. D, iron cycling in the yeast vacuole (Vac) is a combination of Ft and fungal PM iron cycling. The Fe(II) is the input substrate, and Fe(III) is the output substrate with a Ft-like intravacuolar cycling between Fe(II) and Fe(III). All reductions are 1e⁻. Reductions associated with transmembrane iron trafficking involve NADPH-dependent reductases mediated by cytochrome heme centers; the reducing equivalents associated with Ft iron mobilization have not been characterized. All oxidations are catalyzed by a ferroxidase center and consume dioxygen. The question marks indicate that ionic iron speciation in the cytoplasm is largely uncharacterized.

FIGURE 3.

Ferroxidase-iron permease proteins in the eukaryotic PM. Left panel, FRET between yeast Fet3-cyan fluorescent protein (yFet3:CFP) and yeast Ftr1-yellow fluorescent protein (yFtr1:YFP) in the yeast PM. The computer-generated image scores the efficiency of donor quenching by the acceptor from white (∼15%) to magenta (∼50%) (N. Kaur and D. J. Kosman, unpublished data). Right panels, Fpn-green fluorescent protein (Fpn-GFP; upper panel), indirect immunofluorescence of Hp (middle panel), and overlay of images from polarized Caco-2 cells at their basolateral surface (lower panel). This figure was modified from Ref. with permission.