Metal ion transporters in mammals: structure, function and pathological implications

Abstract

Despite the importance of metal ions in several catalytic functions, there has been, until recently, little molecular information available on the mechanisms whereby metal ions are actively taken up by mammalian cells. The classical concept for iron uptake into mammalian cells has been the endocytosis of transferrin‐bound Fe3+ by the transferrin receptor. Studies with hypotransferrinaemic mice revealed that in the intestine mucosal transferrin is derived from the plasma and that its presence is not required in the intestinal lumen for dietary iron absorption. This suggests that, at least in the intestine, other non‐receptor‐mediated uptake systems exist. The molecular identification of metal ion transporters is of great importance, in particular since an increasing number of human diseases are thought to be related to disturbances in metal ion homeostasis, including metal ion overload and deficiency disorders (i.e. anaemia, haemochromatosis, Menkes disease, Wilson's disease), and neurodegenerative diseases (i.e. Alzheimer's, Friedreich's ataxia and Parkinson's diseases). Furthermore, susceptibilities to mycobacterial infections are caused by metal ion transporter defects. The pathological implications of disturbed metal ion homeostasis confirm the vital roles these metal ions play in the catalytic function of many enzymes, in gene regulation (zinc‐finger proteins), and in free radical homeostasis. Recent insights have significantly advanced our knowledge of how metal ions are taken up or released by mammalian cells. The purpose of this review is to summarize these advances and to give an overview on the growing number of mammalian metal ion transporters.

Regulation of transferrin-induced endocytosis by wild-type and C282Y-mutant HFE in transfected HeLa cells

“…Cellular iron uptake by the TfR pathway and its regulation by HFE, the hereditary hemochromatosis gene product, is a complex and only partially understood process (11,29). Previous work has suggested that the expression of wild-type HFE impairs Tf uptake and reduces the affinity of TfR for its ligand Tf (9,16,27,31,32).…”

“…Recent investigations (9,13,26,27,31) indicate a key role of HFE, the hereditary hemochromatosis gene product, in regulating endocytosis of Tf. Hereditary hemochromatosis, one of the most common genetic disorders overall, is characterized by an upregulation of intestinal iron absorption and increased iron deposition in the cytoplasm of parenchymal cells, causing tissue damage and organ failure (14,29). HFE, the responsible gene, was identified in 1996 (8).…”

“…principal mechanism of iron uptake by nonintestinal cells (29). Binding of Tf to the transferrin receptor (TfR) induces rapid formation of clathrin-coated pits and vesicles.…”

DMT1, a physiologically relevant apical Cu1+transporter of intestinal cells

“…In this work we investigated the possibility that copper could also be transported by DMT1, based on the observation that, as with iron, copper induces an inward positive current in oocytes expressing the transporter (12,26). Though the requirement for DMT1 to undertake apical iron absorption and to maintain body iron homeostasis is evident (10,18,25), a putative role for DMT1 in intestinal copper absorption is uncertain.…”

Epithelia & Membrane Transport

“…The balance between cell and matrix zinc distribution in cartilage will be established by zinc carrier proteins. A variety of pathways for zinc permeation have been characterised (Horn et al 1995;Rolfs & Hediger, 1999). In the present study, radioisotope tracer experiments have been performed to establish whether any of these pathways operate in articular chondrocytes.…”