Divalent metal transporter 1 (DMT1) in the brain: implications for a role in iron transport at the blood-brain barrier, and neuronal and glial pathology.

Tina Skjã¸Rringe,Torben Moos,Annette Burkhart,Kasper Bendix Johnsen

doi:10.3389/fnmol.2015.00019

Tina Skjã¸Rringe, Torben Moos + Show 2 more

Open Access

https://doi.org/10.3389/fnmol.2015.00019

Copy DOI

Journal: Frontiers in Molecular Neuroscience	Publication Date: Jun 8, 2015
Citations: 175	License type: cc-by

Affiliation: Aalborg University

Abstract

Iron is required in a variety of essential processes in the body. In this review, we focus on iron transport in the brain and the role of the divalent metal transporter 1 (DMT1) vital for iron uptake in most cells. DMT1 locates to cellular membranes and endosomal membranes, where it is a key player in non-transferrin bound iron uptake and transferrin-bound iron uptake, respectively. Four isoforms of DMT1 exist, and their respective characteristics involve a complex cell-specific regulatory machinery all controlling iron transport across these membranes. This complexity reflects the fine balance required in iron homeostasis, as this metal is indispensable in many cell functions but highly toxic when appearing in excess. DMT1 expression in the brain is prominent in neurons. Of serious dispute is the expression of DMT1 in non-neuronal cells. Recent studies imply that DMT1 does exist in endosomes of brain capillary endothelial cells denoting the blood-brain barrier. This supports existing evidence that iron uptake at the BBB occurs by means of transferrin-receptor mediated endocytosis followed by detachment of iron from transferrin inside the acidic compartment of the endosome and DMT1-mediated pumping iron into the cytosol. The subsequent iron transport across the abluminal membrane into the brain likely occurs by ferroportin. The virtual absent expression of transferrin receptors and DMT1 in glial cells, i.e., astrocytes, microglia and oligodendrocytes, suggest that the steady state uptake of iron in glia is much lower than in neurons and/or other mechanisms for iron uptake in these cell types prevail.

Highlights

We evaluate the literature on uptake and transport of iron in the brain with a focus on delineating the possible roles of divalent metal transporter 1 (DMT1)
The available literature reports on mutations in man, studies on normal and mutated rodent models, and various cellular models manipulating DMT1. We critically evaluate this literature and correlate the functions of DMT1 for iron uptake and transport in the brain with those published in non-neuronal tissues
As DMT1 is thought to play its significant function in concerted action with the transferrin receptor, we place special emphasis on the uptake and transport of iron in brain capillary endothelial cells and neurons, i.e., the two principal cell types with the highest expression of transferrin receptors in the brain (Moos et al, 1998, 2007)

Summary

Introduction

Iron is essential for virtually all eukaryotic cells and indispensable for cellular processes such as DNA synthesis, mitosis, and metabolic processes that require synthesized proteins such as enzymatic reactions and electron transport in the respiratory chainDMT1 in brain (Hentze et al, 2010; Anderson and Vulpe, 2009; Rouault, 2013). As DMT1 is thought to play its significant function in concerted action with the transferrin receptor, we place special emphasis on the uptake and transport of iron in brain capillary endothelial cells and neurons, i.e., the two principal cell types with the highest expression of transferrin receptors in the brain (Moos et al, 1998, 2007).

Results

Conclusion