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Review
. 2019 Feb 19:13:85.
doi: 10.3389/fnins.2019.00085. eCollection 2019.

Deciphering the Iron Side of Stroke: Neurodegeneration at the Crossroads Between Iron Dyshomeostasis, Excitotoxicity, and Ferroptosis

Núria DeGregorio-Rocasolano  1 , Octavi Martí-Sistac  1   2 , Teresa Gasull  1
Affiliations
Review

Deciphering the Iron Side of Stroke: Neurodegeneration at the Crossroads Between Iron Dyshomeostasis, Excitotoxicity, and Ferroptosis

Núria DeGregorio-Rocasolano et al. Front Neurosci. .

Abstract

In general, iron represents a double-edged sword in metabolism in most tissues, especially in the brain. Although the high metabolic demands of brain cells require iron as a redox-active metal for ATP-producing enzymes, the brain is highly vulnerable to the devastating consequences of excessive iron-induced oxidative stress and, as recently found, to ferroptosis as well. The blood-brain barrier (BBB) protects the brain from fluctuations in systemic iron. Under pathological conditions, especially in acute brain pathologies such as stroke, the BBB is disrupted, and iron pools from the blood gain sudden access to the brain parenchyma, which is crucial in mediating stroke-induced neurodegeneration. Each brain cell type reacts with changes in their expression of proteins involved in iron uptake, efflux, storage, and mobilization to preserve its internal iron homeostasis, with specific organelles such as mitochondria showing specialized responses. However, during ischemia, neurons are challenged with excess extracellular glutamate in the presence of high levels of extracellular iron; this causes glutamate receptor overactivation that boosts neuronal iron uptake and a subsequent overproduction of membrane peroxides. This glutamate-driven neuronal death can be attenuated by iron-chelating compounds or free radical scavenger molecules. Moreover, vascular wall rupture in hemorrhagic stroke results in the accumulation and lysis of iron-rich red blood cells at the brain parenchyma and the subsequent presence of hemoglobin and heme iron at the extracellular milieu, thereby contributing to iron-induced lipid peroxidation and cell death. This review summarizes recent progresses made in understanding the ferroptosis component underlying both ischemic and hemorrhagic stroke subtypes.

Keywords: excitotoxicity; ferroptosis; iron; iron dyshomeostasis; neurodegeneration; reactive oxygen species; stroke; transferrin saturation.

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Figures

FIGURE 1
FIGURE 1
Schematic drawing of some of the main players in iron transport to the brain in control (left hand upper side), iron overload (right-hand upper side), ischemic stroke (left-hand lower side), or intracerebral hemorrhage (right-hand lower side). The thicker the arrows the more increased the transport. Abbreviations: ATf, apotransferrin; FPN, ferroportin; HTf, holotransferrin; FT, ferritin, GPX4, glutathione peroxidase 4; GSH, glutathione; Hb, hemoglobin; NTBI, non-transferrin-bound iron; ROS, reactive oxygen species; TJ, tight junction; ZA, zonula occludens.
FIGURE 2
FIGURE 2
Schematic drawing of some of the main players in a neuron under ischemic (left-hand side) and hemorrhagic (right-hand side) stress (see text for details). Abbreviations: APP, amyloid precursor protein; ATf, apotransferrin; CD163, hemoglobin/haptoglobin receptor; CD91, heme/hemopexin receptor; CO, carbon monoxide; CP, ceruloplasmin; DMT1, divalent metal transporter 1; EAAT, excitatory amino acid transporter; Fe2+, ferrous iron; Fe3+, ferric iron; Fe–S, iron–sulfur cluster; FPN, ferroportin; FT, ferritin; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GLS, glutaminase; GPX4, glutathione peroxidase 4; GSH, glutathione; GSSG, glutathione disulfide; Hb, hemoglobin; HFE, hereditary hemochromatosis protein; HIF, hypoxia-inducible factor; HO1, heme oxygenase 1; Hp, haptoglobin; Hpx, hemopexin; HTf, holotransferrin; IRE, iron-responsive element; IRPs, iron regulatory proteins; LIP, labile iron pool; MCOLN1, mucolipin 1; MtFT, mitochondrial ferritin; NCOA, nuclear receptor coactivator; NMDAR, NMDA receptor; NTBI, non-transferrin-bound iron; OH, hydroxyl radical; PCBP, poly(rC)-binding protein; PUFA, poly-unsaturated fatty acid; PUFA-OOH, PUFA peroxide; ROS, reactive oxygen species; Se, selenium; Steap, six-transmembrane epithelial antigen of prostate; system Xc−, cystine–glutamate antiporter; TfR1, transferrin receptor 1; TfR2, transferrin receptor 2; ZIP8/14, zinc transporters 8/14. The picture depicts the effect of one of the major players in the pathophysiology of brain I, the disruption of glutamatergic neurotransmission homeostasis that produces elevated extracellular glutamate levels, overactivation of the NMDA subtype of glutamate receptors (NMDAR), and excitotoxic cell death. In the recent past, different authors have shown that this NMDAR overactivation boosts neuronal iron uptake and produces an iron-dependent form of neuronal death associated with massive lipid peroxidation that fits with the definition of ferroptosis. Further, in the hemorrhage type of stroke, iron derived from hemoglobin and/or heme enters neurons and produces massive lipid peroxidation. Damage by ischemic and hemorrhagic stroke is alleviated by the inhibitors of ferroptosis.
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References

    1. Abergel R. J., Raymond K. N. (2008). Terephthalamide-containing ligands: fast removal of iron from transferrin. J. Biol. Inorg. Chem. 13 229–240. 10.1007/s00775-007-0314-y - DOI - PubMed
    1. Abulrob A., Brunette E., Slinn J., Baumann E., Stanimirovic D. (2011). In vivo optical imaging of ischemic blood-brain barrier disruption. Methods Mol. Biol. 763 423–429. 10.1007/978-1-61779-191-8_29 - DOI - PubMed
    1. Acikyol B., Graham R. M., Trinder D., House M. J., Olynyk J. K., Scott R. J., et al. (2013). Brain transcriptome perturbations in the transferrin receptor 2 mutant mouse support the case for brain changes in iron loading disorders, including effects relating to long-term depression and long-term potentiation. Neuroscience 235 119–128. 10.1016/j.neuroscience.2013.01.014 - DOI - PubMed
    1. Aoyama K., Sang W. S., Hamby A. M., Liu J., Wai Y. C., Chen Y., et al. (2006). Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nat. Neurosci. 9 119–126. 10.1038/nn1609 - DOI - PubMed
    1. Arosio P., Elia L., Poli M. (2017). Ferritin, cellular iron storage and regulation. IUBMB Life 69 414–422. 10.1002/iub.1621 - DOI - PubMed

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