Regulation of Divalent Metal-Ion Transporter-1 Expression and Function

Divalent metal-ion transporter-1 (DMT1) is highly relevant to mineral homeostasis because it potentially transports multiple metal ions, including Fe²⁺, Mn²⁺, Co²⁺, VO²⁺ (vanadyl), Zn²⁺, Cu¹⁺, Ni²⁺, Cd²⁺, and Pb²⁺. The first six ions have physiological relevance; the last three have pathological relevance. DMT1 is a major cellular importer of ferrous ions, both nutritionally and in trafficking. In trafficking it can assist in iron export from the endosome to the mitochondrion during the transferrin cycle and handle iron independent of transferrin. The extent to which it handles other metal ions nutritionally or in trafficking is still uncertain, although it is clear that DMT1 does transport Mn. DMT1 also appears to be involved in sequestering iron to withhold it from infectious species and manage reactive oxygen species. There are four major isoforms defined by transcripts starting at two different promoters and poly-adenylated in two different exons. These result in proteins sharing a common core but distinct in their N- and C-termini. DMT1 expression is highly regulated at transcriptional and posttranscriptional levels and via DMT1 turnover. The isoforms are regulated independently at each of these levels. The occurrence of four isoforms likely reflects employment of DMT1 for differing functions with one isoform specializing in nutritional import in the duodenum. Other isoforms may contribute more to hiding iron from infecting microorganisms or iron distribution by the transferrin cycle.