Transferrin-mediated endocytosis is the primary pathway by which cells obtain iron from plasma. When transferrin (Tf) is highly saturated, as in hemochromatosis, newly absorbed iron from the intestine is present in portal blood as non-Tf bound iron. Non-Tf bound iron is rapidly cleared by the liver and it is assumed that the divalent metal transporter 1 (Dmt1) is responsible for this clearance. Dmt1, along with a surface reductase, mediates cellular uptake of ferrous iron. The Dmt1-reductase system is also present on the luminal surface of enterocytes and mediates absorption of inorganic iron from the diet. Dmt1 plays a second central role in iron delivery to cells by exporting iron liberated from Tf in the acidified endosome into the cytosol. Mice with Dmt1 mutations malabsorb iron and display a microcytic anemia. Parenteral iron does not correct this phenotype because red cells cannot export endosome iron for heme synthesis. Dmt1 is pH-sensitive with optimal activity at pH 5.5. This is consistent with its role in the duodenum and endosome, but the pH of plasma is neutral and Dmt1-mediated iron uptake by the liver would not be efficient. Mice with a disrupted Dmt1 gene (Dmt1-/-) were utilized to determine if cells could import non-Tf iron from plasma in the absence of Dmt1. Tf saturation was elevated in Dmt1 -/-, Dmt1 +/- and Dmt1 +/+ mice by retroorbital injection of iron citrate (FeCit). Ten minutes later, 59Fe was injected into the opposite retroorbital sinus and after an additional 10 min the distribution of radiolabel analyzed. Control Dmt1 +/+ mice injected with PBS followed by 59Fe retained approximately 37% of the total 59Fe counts in blood as Tf(59Fe)2 and 10% of total counts were found in the liver. In contrast, Dmt1 +/+ mice injected with FeCit followed by 59Fe, retained only 3% of total 59Fe in blood and 56% localized to liver. 59Fe distribution in Dmt1 +/- and Dmt1 +/+ was similar. Dmt1-/- mice injected with FeCit followed by 59Fe, retained 16% in blood and 30% in liver. This indicates that Dmt1 -/- mice are able to take up non-Tf iron from the plasma suggesting the presence of an alternate iron transporter(s). Dmt1 +/+ and Dmt1 +/- mice injected with FeCit distributed relatively little 59Fe to the spleen or heart (≤1%). Dmt1 -/- mice had 2.4% and 1.8% respectively in spleen and heart, suggesting a higher level of expression of the putative second transporter in these organs. The findings in Dmt1 -/- mice under conditions of high Tf saturation indicate the presence of an alternate transporter of non-Tf iron that is functional at the neutral pH of plasma.
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