The Metabolism of Neuronal Iron and Its Pathogenic Role in Neurological Disease: Review

Abstract

Neurons need iron, which is reflected in their expression of the transferrin receptor. The concurrent expression of the ferrous iron transporter, divalent metal transporter I (DMT1), in neurons suggests that the internalization of transferrin is followed by detachment of iron within recycling endosomes and transport into the cytosol via DMT1. To enable DMT1-mediated export of iron from the endosome to the cytosol, ferric iron must be reduced to its ferrous form, which could be mediated by a ferric reductase. The presence of nontransferrin-bound iron in brain extracellular fluids suggests that neurons can also take up iron in a transferrin-free form. Neurons are thought to be devoid of ferritin in many brain regions in which there is an association between iron accumulation and cellular damage, for example, neurons of the substantia nigra pars compacta. The general lack of ferritin together with the prevailing expression of the transferrin receptor indicates that iron acquired by activity of transferrin receptors is directed toward immediate use in relevant metabolic processes, is exported, or is incorporated into complexes other than ferritin. Iron has long been considered to play a significant role in exacerbating degradation processes in brain tissue subjected to acute damage and neurodegenerative disorders. In brain ischemia, the damaging role of iron may depend on the inhibition of detoxifying enzymes responsible for catalyzing the oxidation of ferrous iron. Brain ischemia may also lead to an increase in iron supply to neurons as transferrin receptor expression by brain capillary endothelial cells is increased. Pharmacological blockage of the transferrin receptor/DMT1-mediated uptake could be a target to prevent further iron uptake. In chronic neurodegenerative settings, a deleterious role of iron is suggested since cases of Alzheimer's disease, Parkinson's disease, and Huntington's disease have a significantly higher accumulation of iron in affected regions. Dopaminergic neurons are rich in neuromelanin, shown to be more redox-active in Parkinson's disease cases. Iron-containing inflammatory cells may, however, account for the main portion of iron present in neurodegenerative disorders. More knowledge about iron metabolism in normal and diseased neurons is warranted as this may identify pharmaceutical targets to improve neuronal iron management.

Over-expressed human divalent metal transporter 1 is involved in iron accumulation in MES23.5 cells

“…However, whether DMT1 is the cause of iron accumulation is not fully understood. Expression of DMT1 on neurons suggests that they might participate in the iron uptake process in neurons (Suh and Samuel, 2003;Moos and Morgan, 2004;Aracena et al, 2006;Cheah et al, 2006;Shindo et al, 2006). In the present study, we provide direct evidence that increased expression of DMT1 could induce iron uptake.…”

Role and regulation of ferritin H in rotenone-mediated mitochondrial oxidative stress

“…This indicates that an increased amount of Fenton reactions occur during the progression of PD. Also, regions of iron accumulation colocalize with those of neuronal death [42]. Furthermore, iron chelators prevent alpha-synuclein translocation and mitochondrial aggregation, two hallmark events in the pathogenesis of PD [43].…”

Redox Control of Prion and Disease Pathogenesis

“…uptake proteins and increase the content of brain iron, thus creating an ongoing state of oxidative stress (108,114,150). Collectively, this information leaves little doubt that oxidative stress plays a prominent role in prion diseaseassociated neurotoxicity.…”

“…It is believed that a redox-active metal interacts with a specific protein and is reduced in its presence, resulting in the generation of reactive oxygen species (ROS), hydrogen peroxide (H 2 O 2 ), and hydroxyl radicals (OH ) that cause aggregation of the involved protein (16,206,215,224,225). Prominent redoxactive metals that undergo this type of reaction include copper and iron, metals that are often detected in association with protein aggregates specific to AD, PD, and prion disorders (9,150,171,206,252). Whether the accumulation of these metals is a cause or consequence of the disease process is a subject of much dispute.…”