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Titolo Renal iron metabolism: transferrin iron delivery and the role of iron regulatory proteins
Autore D. Zhang, E. Meyron-Holtz, T.A. Rouault
Referenza J Am Soc Nephrol 2007; 18: 401-406
Contenuto In mammalian cells, iron is required for the function of many prosthetic groups, including heme and iron-sulfur clusters. Mammals absorb dietary iron and heme across the apical mucosa of duodenal epithelial cells using a Fe2_ transporter known as divalent metal transporter 1 (DMT-1; also known as solute carrier family 11 member 2, divalent cation transporter 1 (DCT1), and natural resistance associated macrophage protein 2) (1) or a specific heme transporter, heme carrier protein 1 (2). On the basolateral membrane, ferroportin (also known as mental transport protein 1 and iron regulated transporter 1) exports iron to the plasma (3), aided by hephaestin (4), which oxidizes ferrous (Fe2_) to ferric (Fe3_) iron. Serum transferrin (Tf), a 78-kD glycoprotein that is secreted mainly by the liver, binds one or two Fe3_ atoms. Each Fe3_ binds to four amino acid ligands from Tf and additionally binds a carbonate anion that stabilizes iron binding by providing two oxygen ligands. Carbonate binding completes occupancy of the six coordination positions of Fe3_ and thereby stabilizes binding of Fe3_ to Tf. Tf-bound iron circulates freely in the serum and extravascular spaces, and it serves as a source of iron for cells and tissues that are perfused by the systemic circulation, including liver, heart, muscle, kidney, and bone marrow (5). Excess intracellular iron is stored in ferritin, a heteropolymeric molecule that has a spherical shell structure and is composed of 24 H and L subunits, which can store up to 4500 iron atoms as a mineral core inside the shell (6). Iron can be released from ferritin when cells need more iron either when ferritin is degraded in the lysosome (7) or through a pore in the ferritin shell (8). Most cells modulate iron uptake by regulating the amount of Tf receptor 1 (TfR1) (9) that they express on the plasma membrane. The TfR functions as a dimer, and each 90-kD monomer has a single transmembrane-spanning domain. Upon binding iron-bearing Tf, the TfR-Tf complex is internalized into an early endosome, where acidification facilitates release of Fe3_ from Tf and a reductase reduces Fe3_ to Fe2_ (10), which then can be exported into cytosol by DMT-1 in the late endosomal/lysosomal compartment. A second TfR that is expressed mainly by hepatocytes, TfR2, is not regulated by intracellular iron levels and is unlikely to be important in renal iron metabolism (11).
Data 15.03.2007
 
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