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. 2013 Jul 18:5:34.
doi: 10.3389/fnagi.2013.00034. eCollection 2013.

A delicate balance: Iron metabolism and diseases of the brain

Dominic Hare  1 , Scott Ayton, Ashley Bush, Peng Lei
Affiliations

A delicate balance: Iron metabolism and diseases of the brain

Dominic Hare et al. Front Aging Neurosci. .

Abstract

Iron is the most abundant transition metal within the brain, and is vital for a number of cellular processes including neurotransmitter synthesis, myelination of neurons, and mitochondrial function. Redox cycling between ferrous and ferric iron is utilized in biology for various electron transfer reactions essential to life, yet this same chemistry mediates deleterious reactions with oxygen that induce oxidative stress. Consequently, there is a precise and tightly controlled mechanism to regulate iron in the brain. When iron is dysregulated, both conditions of iron overload and iron deficiencies are harmful to the brain. This review focuses on how iron metabolism is maintained in the brain, and how an alteration to iron and iron metabolism adversely affects neurological function.

Keywords: Alzheimer’s disease; Parkinson’s disease; iron chelation; iron deficiency; iron regulation.

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Figures

FIGURE 1
FIGURE 1
Neuronal iron uptake and export. Iron is imported into the cell either as low molecular weight complexes with citrate/ATP, or via transferrin receptor (TfR1)-mediated endocytosis (1). Export of iron from the endosome via divalent metal transporter-1 (DMT-1) directly contributes to the labile iron pool (2), which constitutes the available iron content of the neuron and is regulated by cellular metal sensing and iron-binding protein expression, including ferritin, which is the major iron storage protein in neurons (3). Export of iron from neurons is regulated by intramembrane ferroportin, which is stabilized via a mechanism involving tau and ceruloplasmin (Cp)/APP (4). Iron is then recirculated by apo-Tf (5).
FIGURE 2
FIGURE 2
Factors influencing cellular iron metabolism. Cellular oxygen homeostasis regulates iron metabolism in the nucleus via the hypoxia inducible factors (HIF-1α and -1β). In normoxia conditions, Fe2+ mediates the hydroxylation of proline residue 546 on HIF-1α by prolyl-4-hydroxylase (PHD), which enables ubiquitination via binding with the von Hippel–Lindau tumor suppressor gene product (VHL). Decreased HIF-1α inhibits transcription of proteins dictating iron uptake and export. In the iron-deficient cell, HIF-1α instead interacts with CREB binding protein/p300 (CBP/p300) and forms a heterodimer with HIF-1β, activating transcription of target genes possessing hypoxia response elements. In the cytosol, the iron replete cell prevents the binding of iron responsive proteins (IRP) -1 and -2 to the iron responsive elements (IREs) in the 5′ and 3′ untranslated region (UTR) of mRNA, inhibiting the transcription of uptake proteins and promoting expression of proteins involved in iron export. In cases of iron deficiency, IRPs directly interact with the 5′- and 3′-UTRs, eliciting the reverse effect. TfR, transferrin receptor; DMT-1, divalent metal transporter-1; APP, amyloid precursor protein.
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References

    1. Abbott N. J., Rönnbäck L., Hansson E. (2006). Astrocyte–endothelial interactions at the blood–brain barrier. Nat. Rev. Neurosci. 7 41–53 - PubMed
    1. Abboud S., Haile D. J. (2000). A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J. Biol. Chem. 275 19906–19912 10.1074/jbc.M000713200 - DOI - PubMed
    1. Abbruzzese G., Cossu G., Balocco M., Marchese R., Murgia D., Melis M., et al. (2011). A pilot trial of deferiprone for neurodegeneration with brain iron accumulation. Haematologica 96 1708–1711 10.3324/haematol.2011.043018 - DOI - PMC - PubMed
    1. Adlard P. A., Cherny R. A., Finkelstein D. I., Gautier E., Robb E., Cortes M., et al. (2008). Rapid restoration of cognition in Alzheimer’s transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron 59 43–55 10.1016/j.neuron.2008.06.018 - DOI - PubMed
    1. Aisen P. (2001). Chemistry and biology of eukaryotic iron metabolism. Int. J. Biochem. Cell Biol. 33 940–959 10.1016/S1357-2725(01)00063-2 - DOI - PubMed

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