DMT1 as a candidate for non‐transferrin‐bound iron uptake in the peripheral nervous system

Abstract

Iron, either in its chelated form or as holotransferrin (hTf), prevents the dedifferentiation of Schwann cells (SC), cells responsible for the myelination of the peripheral nervous system (PNS). This dedifferentiation is promoted by serum deprivation through cAMP release, PKA activation, and CREB phosphorylation. Since iron elicits its effect in a transferrin (Tf)-free environment, in this work we postulate that non-transferrin-bound iron (NTBI) uptake must be involved. Divalent metal transporter 1(DMT1) has been widely described in literature as a key player in iron metabolism, but never before in the PNS context. The presence of DMT1 was demonstrated in nerve homogenate, isolated adult-rat myelin, and cultured SC by Western Blot (WB) analysis and confirmed through its colocalization with S-100β (SC marker) by immunocytochemical and immunohistochemical analyses. Furthermore, the existence of its mRNA was verified in sciatic nerve homogenate by RT-PCR and throughout SC maturational stages. Finally, we describe DMT1's subcellular location in the plasma membrane by confocal microscopy of SC and WB of different subcellular fractions. These data allow us to suggest the participation of DMT1 as part of a Tf independent iron uptake mechanism in SC and lead us to postulate a crucial role for iron in SC maturation and, as a consequence, in PNS myelination.

DMT1 iron uptake in the PNS: bridging the gap between injury and regeneration

“…Furthermore, we have recently shown the presence of DMT1 in the SC plasma membrane in vivo and in vitro, which suggests its participation in cellular iron uptake. 8 DMT1 is a four-isoform protein -including two iron-responsiveelement-positive (IRE+) and two IREÀ isoforms -ubiquitously expressed at systemic and cellular levels. It is generally regarded as one of the major transport proteins for iron uptake and considered sensitive to a wide range of normal and abnormal circumstances regarding damage and adaptive mechanisms involved in recovery.…”

Iron Metabolism in the Peripheral Nervous System: The Role of DMT1, Ferritin, and Transferrin Receptor in Schwann Cell Maturation and Myelination

“…DMT1 is crucial for iron uptake and normal SC maturation DMT1 is indispensable for dietary-iron absorption in the intestine but also constitutes a crucial component of the transferrin cycle by mediating ferrous iron transport across the endosomal membrane (Gunshin et al, 2005). In the sciatic nerve, SCs show elevated levels of DMT1 in the plasma membrane as well as in the nucleus (Vivot et al, 2013), and higher DMT1 quantities were found in SCs near demyelinated lesions (Vivot et al, 2015). We have recently established that DMT1 is essential for proper oligodendrocyte maturation and is required for an efficient remyelination of the adult brain (Cheli et al, 2018).…”

“…DMT1 is a proton-driven metal transporter primarily responsible for iron transport from endosomes as well as for diet iron uptake in the gut (Gruenheid et al, 1995;Veuthey and Wessling-Resnick, 2014). DMT1 is expressed by neurons (Skjørringe et al, 2015), astrocytes (Erikson and Aschner, 2006;Song et al, 2007), and oligodendrocytes in the brain (Burdo et al, 2001, Cheli et al, 2018; and by SCs in the PNS (Vivot et al, 2013).…”

Iron Homeostasis in Peripheral Nervous System, Still a Black Box?

“…A very recent article indicated dimetal transporter 1 (DMT1), a Fe 2 + transporter responsible for iron uptake from the gut and transport from endosomes, as another candidate of nontransferrin bound iron (NTBI) acquisition within the PNS (151). By immunotechniques, the authors showed the presence of DMT1 in nerve homogenate, isolated from adult rat and in cultured SC, where it localizes on the plasma membrane (151).…”

“…By immunotechniques, the authors showed the presence of DMT1 in nerve homogenate, isolated from adult rat and in cultured SC, where it localizes on the plasma membrane (151). Unfortunately, they did not show any data on the specificity of the commercially available antibody used in immunofluorescence experiments, making the observation not exhaustive.…”