Cellular iron efflux involves the sole known iron exporter Ferroportin, highly expressed in
- duodenal cells
- hepatocytes
- macrophages
- placental cells
and a ferrioxidase: hephaestin / ceruloplasmin , copper containing enzymes, that oxidize ferrous iron to the ferric form.
Ferroportin, is post-translationally regulated by hepcidin, a circulating peptide hormone.
Iron release
Iron is released by FPN as Fe2+. The exiting iron is re-oxidised to Fe3+ through hephaestin (Hp) to enable loading onto transferrin (Tf). (Transferrin cycle)
Hepcidin causes the degradation of ferroportin , thereby blocking iron flow into plasma (Regulation of iron metabolism by Hepcidin).
Ferroportin localization:
Depending on its subcellular localizations, ferroportin can modulate the direction of iron export from the cells.
Differences in apparent molecular masses were partly explained by posttranslational complex N-linked glycosylations.
Duodenal enterocytes
Ferroportin is highly expressed in absorptive duodenal enterocytes where it presents a strong basolateral subcellular localization. Several lines of evidence indicate that in enterocytes the iron export mediated by ferroportin occurs and is regulated at the basolateral cell surface, where the transporter is strongly expressed.
Ferroportin is particularly expressed at the tip of the villus rather than the crypt.
However, while ferroportin1 is expressed in the duodenum, it is not produced in either the jejunum or ileum. [Nghia TV et al, 2001]
Macrophages
Ferroportin is highly expressed in tissue macrophages in liver (Kupffer cells), spleen, and bone marrow.
In quiescent macrophages, ferroportin has been shown predominantly in intracellular vesicles.
Ferroportin is expressed in vesicular compartments that can reach the plasma membrane of macrophages.
When ferroportin expression was up-regulated through iron treatment or erythrophagocytosis, ferroportin expression was strongly enhanced at the plasma membrane of macrophages. [F Canonne-Hergaux et al, 2005; C Delaby et al, 2005]
Placental cells
Ferroportin1 was also readily detected at the basolateral surface of placental syncytiotrophoblasts , which interfaces with the fetal circulation (the apical surface of these cells interface with the maternal circulation). Furthermore, the expression of ferroportin1 in placental tissue is highest during the third trimester of pregnancy and is developmentally regulated. This suggests a possible role for ferroportin1 in Fe transport from the mother to the developing fetus. [Nghia TV et al, 2001]
Lung
Ferroportin is present at a high level in airway epithelial cells and alveolar macrophages , but not in other lung cells.
Ferroportin is located uniquely on the apical but not basolateral membrane of these cells in both human and rodent lungs.
Ferroportin expression is upregulated in airway epithelial cells when exposed to iron in a dosage-responsive manner.
While in duodenal epithelia DMT1 mediated iron uptake across the apical membrane and FPN1 mediated iron export across the basolateral membrane into the circulation to nonheme nutritional iron absorption , in airway epithelia DMT1 mediated nontransferrin- bound iron uptake from airway lumen and FPN1 mediated export of iron across the apical membrane into the lumen as protein-bound complexes to iron detoxification. [Apical location of ferroportin 1 in airway epithelia and its role in iron detoxification in the lung , 2005; Ghio AJ ferroportin lung
Brain
The first step in blood to brain transport of iron is receptor-mediated endocytosis of transferrin, transferrin receptors are present on brain capillary endothelial cells (BCECs). Iron is probably released from transferrin on the abluminal surface of these cells by the action of citrate and ATP that are released by astrocytes, which form a very close relationship with BCECs.
Complexes of iron with citrate and ATP can then circulate in brain extracellular fluid and may be taken up in these low molecular weight forms by all types of brain cells or be bound by transferrin and taken up by cells which express transferrin receptors. [T Moos et al, 2007]
Neurons contain both transferrin receptors and DMT1 and can take up transferrin-bound iron. Neurons express ferroportin, which probably allows them to excrete unneeded iron. Neuronal ferroportin is virtually ubiquitously expressed in the brain suggests that iron-export mediated by ferroportin is a permanently active mechanism, which ensures iron-homeostasis inside the neuron. Iron is thought to undergo axonal and dendritic transport, and as ferroportin is found in the somata, axons, and dendrites of neurons, it probably plays an important role to regulate iron levels everywhere in the neuron.
APP can replace Ceruloplasmin in neurons
Iron-Export Ferroxidase Activity of β- Amyloid Precursor Protein Is Inhibited by Zinc in Alzheimer's Disease 2010
Macroglia:
Astrocytes lack transferrin receptors. Their source of iron is probably that released from transferrin on the abluminal surface of BCECs. They probably to export iron by a mechanism involving a membrane-bound form of the ferroxidase, ceruloplasmin.
Oligodendrocytes also lack transferrin receptors. They probably take up non-transferrin bound iron that gets incorporated in newly synthesized transferrin, which may play an important role for intracellular iron transport. In contrast to astrocytes, oligodendrocytes contain ferroportin, indicating that they can export iron as part of their regulation of intracellular ironhomeostasis.
Microglia , in contrast to monocytes and macrophages, do not contain ferroportin.
Iron oxidation by Copper Ferroxidases
Ceruloplasmin/Macrophages ???
Haephestin/Enterocytes ???
