DMT1 Expression and Iron Levels at the Crossroads Between Aging and Neurodegeneration.

Rosaria Ingrassia,Barbara Garavaglia,Maurizio Memo

doi:10.3389/fnins.2019.00575

Abstract

Iron homeostasis is an essential prerequisite for metabolic and neurological functions throughout the healthy human life, with a dynamic interplay between intracellular and systemic iron metabolism. The development of different neurodegenerative diseases is associated with alterations of the intracellular transport of iron and heavy metals, principally mediated by Divalent Metal Transporter 1 (DMT1), responsible for Non-Transferrin Bound Iron transport (NTBI). In addition, DMT1 regulation and its compartmentalization in specific brain regions play important roles during aging. This review highlights the contribution of DMT1 to the physiological exchange and distribution of body iron and heavy metals during aging and neurodegenerative diseases. DMT1 also mediates the crosstalk between central nervous system and peripheral tissues, by systemic diffusion through the Blood Brain Barrier (BBB), with the involvement of peripheral iron homeostasis in association with inflammation. In conclusion, a survey about the role of DMT1 and iron will illustrate the complex panel of interrelationship with aging, neurodegeneration and neuroinflammation.

Highlights

Interest in the contribution of iron and Divalent Metal Transporter 1 (DMT1) to both aging and neurodegeneration comes from relevant studies performed during the course of the last 20 years
DMT1 principally mediates the transport of ferrous iron and heavy metals in systemic iron homeostasis, from the plasma membrane or endosomes to the intracellular labile pool, mostly sustaining Non-Transferrin Bound Iron transport (NTBI)
According to recent highlights, the uptake of NTBI into the liver seems to be mediated by ZIP14/SLC39A14 (Jenkitkasemwong et al, 2012) and hepatocyte DMT1 was shown to be dispensable for hepatic iron accumulation (Wang and Knutson, 2013)

Summary

Introduction

Interest in the contribution of iron and DMT1 to both aging and neurodegeneration comes from relevant studies performed during the course of the last 20 years. DMT1 mRNA was found up-regulated in the cerebellum of ceruloplasmin-knockout mice, in Purkinje and deep nuclei neurons (Jeong and David, 2006), in the frontal cortex of both wild-type and APPSWE/PS1 E9 Alzheimer mouse model (Xian-hui et al, 2015), and (+)/(–) IRE DMT1 isoforms significantly increased in rat cortex, striatum, hippocampus and substantia nigra (Lu et al, 2017).

Results

Conclusion