Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver

Abstract

Solute carrier family 11, member 2 (SLC11A2) is the only transmembrane iron transporter known to be involved in cellular iron uptake. It is widely expressed and has been postulated to play important roles in intestinal iron absorption, erythroid iron utilization, hepatic iron accumulation, placental iron transfer, and other processes. Previous studies have suggested that other transporters might exist, but their physiological significance remained uncertain. To define the activities of Slc11a2 in vivo, we inactivated the murine gene that encodes it globally and selectively. We found that fetal Slc11a2 is not needed for materno-fetal iron transfer but that Slc11a2 activity is essential for intestinal non-heme iron absorption after birth. Slc11a2 is also required for normal hemoglobin production during the development of erythroid precursors. However, hepatocytes and most other cells must have an alternative, as-yet-unknown, iron uptake mechanism. We previously showed that Slc11a2 serves as the primary portal for intestinal iron entry in hemochromatosis. However, inactivation of murine Hfe ameliorates the phenotype of animals lacking Slc11a2.

DMT1-Mutant Erythrocytes have Shortened Life Span, Accelerated Glycolysis and Increased Oxidative Stress

“…Heterozygous mice bearing the G185R DMT1 mutation ( mk /+, strain 129S6/SvEvTac) [1] were provided by M. Fleming (Children's Hospital, Boston, USA). Mice were fed a standard diet; 10- to 16-week-old mk/mk mice and their wild-type (wt) littermates were included in the study.…”

“…Divalent metal transporter 1 (DMT1; also known as NRAMP2 and SLC11A2) is an intestinal and endosomal iron (Fe 2+ ) transporter [1]. Mutations inactivating DMT1 are associated with a severe defect in erythroid iron utilization and cause moderate to severe hypochromic microcytic anemia in human patients [2,3,4,5,6] and two rodent models, mk/mk mice [7] and Belgrade rats [8].…”

“…Mutations inactivating DMT1 are associated with a severe defect in erythroid iron utilization and cause moderate to severe hypochromic microcytic anemia in human patients [2,3,4,5,6] and two rodent models, mk/mk mice [7] and Belgrade rats [8]. In addition, DMT1 knockout animals ( Slc11a2 -/- ) die in the first week of life due to iron deficient erythropoiesis [1]. …”

Physiology of Iron Metabolism

“…DMT1 is the most important transporter of ferrous iron (Fe 2+ ), [80,81]. Of note, ferric reductase activities due to duodenal cytochrome B [82] and STEAPs (six transmembrane epithelial antigen of the prostate proteins) [83] are present on the brush border of duodenum allowing reduction of ferric to ferrous iron, thus facilitating its absorption by DMT1.…”

Mammalian iron transport

“…Indeed, it was the search for the protein that mediated the uptake of iron by the intestinal epithelium that initially led to the identification of DMT1 [56,58]. The placenta must also transport large amounts of iron and it is a prominent site of DMT1 expression, although interestingly it does not appear to be essential for placental iron transport [63]. Iron uptake following TfR2-mediated endocytosis, the surface delivery of Tf-derived iron, and the uptake of NTBI are also likely to utilize DMT1 [12,54,64].…”