| Divalent metal transporter 1 (DMT1, also known as SLC11A2, NRAMP2, or DCT1) is a proton‑coupled divalent cation transporter that serves as the principal transmembrane route for ferrous iron uptake at the apical border of duodenal enterocytes and for iron exit from transferrin endosomes in multiple cell types, placing it at the core of non‑heme iron acquisition and cellular iron handling. The protein is a multipass membrane transporter with twelve predicted transmembrane helices and cytosolic N‑ and C‑termini, and alternative splicing and differential use of iron‑responsive elements generate isoforms with distinct subcellular localization and post‑transcriptional regulation, allowing DMT1 to operate both at the plasma membrane and on endosomal membranes in tissue‑specific patterns. Transport activity couples inward proton movement to uptake of divalent metals, with highest preference for Fe²⁺ and a pH optimum in the mildly acidic range that matches the duodenal lumen and endosomal compartments, and DMT1 also carries Mn²⁺ and other first‑row transition metals with lower selectivity, providing a shared pathway for nutritionally essential and potentially toxic metals. At the intestinal brush border, ferrireductases and dietary reductants convert luminal Fe³⁺ to Fe²⁺, which DMT1 then transports into enterocytes, while on the transferrin cycle endosomes in erythroid precursors and other cells, DMT1 mediates release of Fe²⁺ from endosomes into the cytosol after transferrin‑bound iron is reduced, supplying iron for heme synthesis, iron–sulfur cluster assembly, and iron storage. Expression of DMT1 responds to intracellular iron status through iron‑responsive element–dependent and –independent mechanisms and is modulated by systemic regulators of iron metabolism, aligning transporter abundance with body iron demand and integrating DMT1 into the hepcidin–ferroportin axis of iron homeostasis. DMT1 is also present in brain microvascular endothelium, neurons, and glia, where it is implicated in iron entry across the blood–brain barrier, neuronal iron uptake, and manganese transport, creating a link between DMT1 function, regional brain iron loading, and the vulnerability of dopaminergic and other neuronal populations to oxidative stress in aging and neurodegeneration. Mutations or functional depletion of DMT1 in rodents cause hypochromic microcytic anemia with impaired intestinal iron absorption and defective erythroid iron utilization, while the characterized human loss‑of‑function mutation produces severe anemia with abnormal iron handling in erythroid cells, underscoring the requirement for DMT1‑mediated ferrous iron transport for both dietary uptake and erythropoiesis. In contrast, increased DMT1 expression or activity is associated with iron overload in select tissues and with elevated brain iron and manganese in experimental models, where excess metal accumulation contributes to mitochondrial dysfunction, reactive oxygen species formation, and neurodegenerative changes, and DMT1 has been implicated as a contributor to the iron and manganese imbalance observed in disorders such as Parkinson’s disease and other neurodegenerative conditions. |
