Intestinal brush-border Na+/H+ exchanger-3 drives H+-coupled iron absorption in the mouse.

Divalent metal-ion transporter-1 (DMT1), the principal mechanism by which nonheme iron is taken up at the intestinal brush border, is energized by the H(+)-electrochemical potential gradient. The provenance of the H(+) gradient in vivo is unknown, so we have explored a role for brush-border Na(+)/H(+) exchanger (NHE) isoforms by examining iron homeostasis and intestinal iron handling in mice lacking NHE2 or NHE3. We observed modestly depleted liver iron stores in NHE2-null (NHE2(-/-)) mice stressed on a low-iron diet but no change in hematological or blood iron variables or the expression of genes associated with iron metabolism compared with wild-type mice. Ablation of NHE3 strongly depleted liver iron stores, regardless of diet. We observed decreases in blood iron variables but no overt anemia in NHE3-null (NHE3(-/-)) mice on a low-iron diet. Intestinal expression of DMT1, the apical surface ferrireductase cytochrome b reductase-1, and the basolateral iron exporter ferroportin was upregulated in NHE3(-/-) mice, and expression of liver Hamp1 (hepcidin) was suppressed compared with wild-type mice. Absorption of (59)Fe from an oral dose was substantially impaired in NHE3(-/-) compared with wild-type mice. Our data point to an important role for NHE3 in generating the H(+) gradient that drives DMT1-mediated iron uptake at the intestinal brush border.

H(+)-coupled divalent metal-ion transporter-1: functional properties, physiological roles and therapeutics.

Divalent metal-ion transporter-1 (DMT1) is a widely expressed, iron-preferring membrane transport protein. Animal models establish that DMT1 plays indispensable roles in intestinal nonheme-iron absorption and iron acquisition by erythroid precursor cells. Rare mutations in human DMT1 result in severe microcytic-hypochromic anemia. When we express DMT1 in RNA-injected Xenopus oocytes, we observe rheogenic Fe(2+) transport that is driven by the proton electrochemical potential gradient. In that same preparation, DMT1 also transports cadmium and manganese but not copper. Whether manganese metabolism relies upon DMT1 remains unclear but DMT1 contributes to the effects of overexposure to cadmium and manganese in some tissues. There exist at least four DMT1 isoforms that arise from variant transcription of the SLC11A2 gene. Whereas these isoforms display identical functional properties, N- and C-terminal variations contain cues that direct the cell-specific targeting of DMT1 isoforms to discrete subcellular compartments (plasma membrane, endosomes, and lysosomes). An iron-responsive element (IRE) in the mRNA 3'-untranslated region permits the regulation of some isoforms by iron status, and additional mechanisms by which DMT1 is regulated are emerging. Natural-resistance-associated macrophage protein-1 (NRAMP1)-the only other member of the mammalian SLC11 gene family-contributes to antimicrobial function by extruding from the phagolysosome divalent metal ions (e.g. Mn(2+)) that may be essential cofactors for bacteria-derived enzymes or required for bacterial growth. The principal or only intestinal nonheme-iron transporter, DMT1 is a validated therapeutic target in hereditary hemochromatosis (HHC) and other iron-overload disorders.