Divalent Metal Transport Mechanisms in Neurodegenerative Disorders

Neuronal survival and function depend critically on the controlled uptake, intracellular trafficking and export of divalent metals, most notably iron and manganese. In healthy brain tissue, transporters such as the divalent metal transporter 1 (DMT1) and ferroportin mediate uptake and release of ferrous iron (Fe2+), while specialised endosomal and lysosomal pathways regulate its distribution to mitochondria, synaptic vesicles and cytosolic stores. At the blood–brain barrier, endothelial cells employ transferrin receptor-mediated endocytosis alongside DMT1 to ensure iron supply, whereas glial cells rely on alternative routes for local homeostasis. Dysregulation of these pathways is a hallmark of Alzheimer’s, Parkinson’s and other protein-aggregation disorders, in which elevated labile iron pools catalyse oxidative stress and lipid peroxidation, contributing to cell death by ferroptosis. In addition, inflammatory signals and nitric oxide modulate iron regulatory proteins and post-translational modification of transporters, further disturbing metal balance. Emerging evidence highlights the dual role of DMT1 not only in non-transferrin bound iron uptake but also in mitochondrial acquisition of both iron and manganese, thereby influencing bioenergetic competence and reactive oxygen species generation. Therapeutic strategies aimed at modulating transporter expression, enhancing endosomal trafficking or chelating labile iron offer promise for slowing neurodegenerative progression and mitigating global disease burden.

Research from Nature Portfolio

Recent foundational work has established DMT1 localisation to the outer mitochondrial membrane, identifying it as a primary conduit for ferrous iron and manganese entry into mitochondria. Using inducible expression systems in human cell lines, investigators demonstrated that overexpression of DMT1 enhances Fe2+ and Mn2+ uptake in a proton-gradient-dependent manner, with kinetic affinities in the low micromolar range. Inhibition of DMT1 markedly reduces non-haem iron accumulation and diminishes mitochondrial metal import, confirming the transporter’s direct role. These findings expand the mechanistic understanding of intracellular metal trafficking, linking DMT1 activity to both energy metabolism and redox homeostasis, and suggest mitochondrial DMT1 as a novel target for intervention in metal-associated neurodegeneration.

Divalent Metal Transport Mechanisms in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in divalent metal transport mechanisms in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Divalent Metal Transporter 1 (DMT1): A membrane protein that mediates cellular uptake of non-transferrin bound ferrous iron and manganese.

Blood–Brain Barrier (BBB): A selective endothelial interface that regulates passage of ions, nutrients and metals into the central nervous system.

Labile Iron Pool (LIP): The cytosolic, redox-active fraction of iron available for metabolic reactions but capable of catalysing free-radical formation.

Ferroptosis: A form of regulated cell death driven by iron-dependent lipid peroxidation.

Ischaemic Neurodegeneration: Neuronal injury resulting from insufficient blood supply, leading to energy failure and metal-mediated oxidative damage.

References

1. A role for divalent metal transporter (DMT1) in mitochondrial uptake of iron and manganese. Scientific Reports (2018).
2. Ischemic Neuroprotection by Insulin with Down-Regulation of Divalent Metal Transporter 1 (DMT1) Expression and Ferrous Iron-Dependent Cell Death. Biomolecules (2024).
3. DMT1 Expression and Iron Levels at the Crossroads Between Aging and Neurodegeneration. Frontiers in Neuroscience (2019).
4. Nitric Oxide, Iron and Neurodegeneration. Frontiers in Neuroscience (2019).
5. 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. Frontiers in Molecular Neuroscience (2015).