Divalent metal-ion transporter DMT1 mediates both H+ -coupled Fe2+ transport and uncoupled fluxes

Bryan Mackenzie, M. L. Ujwal, Min Hwang Chang, Michael F. Romero, Matthias A. Hediger

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

Abstract

The H+ -coupled divalent metal-ion transporter DMT1 serves as both the primary entry point for iron into the body (intestinal brush-border uptake) and the route by which transferrin-associated iron is mobilized from endosomes to cytosol in erythroid precursors and other cells. Elucidating the molecular mechanisms of DMT1 will therefore increase our understanding of iron metabolism and the etiology of iron overload disorders. We expressed wild type and mutant DMT1 in Xenopus oocytes and monitored metal-ion uptake, currents and intracellular pH. DMT1 was activated in the presence of an inwardly directed H+ electrochemical gradient. At low extracellular pH (pH o), H+ binding preceded binding of Fe2+ and its simultaneous translocation. However, DMT1 did not behave like a typical ion-coupled transporter at higher pHo, and at pHo 7.4 we observed Fe2+ transport that was not associated with H+ influx. His272 → Ala substitution uncoupled the Fe2+ and H+ fluxes. At low pHo, H272A mediated H+ uniport that was inhibited by Fe2+. Meanwhile H272A-mediated Fe 2+ transport was independent of pHo. Our data indicate (i) that H+ coupling in DMT1 serves to increase affinity for Fe 2+ and provide a thermodynamic driving force for Fe2+ transport and (ii) that His-272 is critical in transducing the effects of H + coupling. Notably, our data also indicate that DMT1 can mediate facilitative Fe2+ transport in the absence of a H+ gradient. Since plasma membrane expression of DMT1 is upregulated in liver of hemochromatosis patients, this H+ -uncoupled facilitative Fe 2+ transport via DMT1 can account for the uptake of nontransferrin-bound plasma iron characteristic of iron overload disorders.

Original languageEnglish (US)
Pages (from-to)544-558
Number of pages15
JournalPflugers Archiv European Journal of Physiology
Volume451
Issue number4
DOIs
StatePublished - Jan 2006

Keywords

  • Cotransporters
  • Iron overload
  • Iron transport
  • Metal-ion transport
  • Oocyte
  • Proton-coupled transport
  • Xenopus laevis
  • Zinc transport

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

Fingerprint

Dive into the research topics of 'Divalent metal-ion transporter DMT1 mediates both H<sup>+</sup> -coupled Fe<sup>2+</sup> transport and uncoupled fluxes'. Together they form a unique fingerprint.

Cite this