Iron metabolism in the eye: A review

Goralska, M.; Ferrell, J.; Harned, J.; Lall, Marilyn M.; Nagar, Steven; Fleisher, Lloyd N.; McGahan, M.C.

doi:10.1016/j.exer.2008.10.026

Cited by 45 publications

(47 citation statements)

References 168 publications

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“…Binding of holo-Tf to TfR2 results in a structural shift in the TfR2 protein, resulting in the release of HFE into the cytosol. This allows HFE to regulate other iron homeostasis proteins (Goralska et al, 2009). In contrast to TBI, NTBI import machinery brings labile, extracellular ferrous iron directly across the plasma membrane without moving through the Tf-TfR endosomal complex.…”

Section: Introductionmentioning

confidence: 99%

Iron importers Zip8 and Zip14 are expressed in retina and regulated by retinal iron levels

Sterling

Guttha

Song

et al. 2017

Experimental Eye Research

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Intracellular retinal iron accumulation has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of irreversible blindness among individuals over the age of 50. Ceruloplasmin/hephaestin double knockout mice (Cp/Heph DKO) and hepcidin knockout mice (Hepc KO) accumulate retinal iron and model some features of AMD. Two canonical pathways govern cellular iron import – transferrin-bound iron import and non-transferrin bound iron import. In Cp/Heph DKO and Hepc KO iron-loaded retinas, transferrin-bound iron import is downregulated. Despite this effort to reduce cellular iron burden, iron continues to accumulate in these retinas in an age-dependent manner. Quantitative RT-PCR and Western analysis were used to quantify the expression of three ferrous iron importers, Dmt1, Zip8, and Zip14, in wild-type (Wt), Cp/Heph DKO, and Hepc KO retinas. Zip8 and Zip14 protein levels were analyzed using Western analysis in mice injected intravitreally with either apo- or holo-transferrin to elucidate one possible mechanism of Zip14 regulation in the retina. Both zip8 and zip14 were expressed in the mouse retina. Paradoxically, protein levels of non-transferrin bound iron importers were upregulated in both Cp/Heph DKO and Hepc KO retinas. Intravitreal holo-transferrin injection decreased Zip 14 protein levels. These data indicate that Zip8 and Zip14 may take up increasing amounts of non-transferrin bound iron in these two mouse models of retinal iron accumulation. Their upregulation in these already iron-loaded retinas suggests a vicious cycle leading to toxicity.

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Section: Introductionmentioning

confidence: 99%

Iron importers Zip8 and Zip14 are expressed in retina and regulated by retinal iron levels

Sterling

Guttha

Song

et al. 2017

Experimental Eye Research

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“…Here, we investigated the role of α-syn in iron uptake by RPE cells, the site of dopamine synthesis and an integral component of the outer blood-retinal barrier that separates the neuroretina from fenestrated choroidal capillaries [50, 56, 57]. The polarized nature of these cells confers distinct structural and functional properties to each domain necessary for their specialized function.…”

Section: Introductionmentioning

confidence: 99%

Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrin-bound iron: Implications for visual manifestations of Parkinson's disease

Baksi

Tripathi

Singh

2016

Free Radical Biology and Medicine

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Aggregation of α-synuclein (α-syn) in neurons of the substantia nigra is diagnostic of Parkinson’s disease (PD), a neuro-motor disorder with prominent visual symptoms. Here, we demonstrate that α-syn, the principal protein involved in the pathogenesis of PD, is expressed widely in the neuroretina, and facilitates the uptake of transferrin-bound iron (Tf-Fe) by retinal pigment epithelial (RPE) cells that form the outer blood-retinal barrier. Absence of α-syn in knock-out mice (α-syn−/−) resulted in down-regulation of ferritin in the neuroretina, indicating depletion of cellular iron stores. A similar phenotype of iron deficiency was observed in the spleen, femur, and brain tissue of α-syn−/− mice, organs that utilize mainly Tf-Fe for their metabolic needs. The liver and kidney, organs that take up significant amounts of non-Tf-bound iron (NTBI), showed minimal change. Evaluation of the underlying mechanism in the human RPE47 cell line suggested a prominent role of α-syn in the uptake of Tf-Fe by modulating the endocytosis and recycling of transferrin (Tf)/transferrin-receptor (TfR) complex. Down-regulation of α-syn in RPE cells by RNAi resulted in the accumulation of Tf/TfR complex in common recycling endosomes (CREs), indicating disruption of recycling to the plasma membrane. Over-expression of exogenous α-syn in RPE cells, on the other hand, up-regulated ferritin and TfR expression. Interestingly, exposure to exogenous iron increased membrane association and co-localization of α-syn with TfR, supporting its role in iron uptake by the Tf/TfR complex. Together with our observations indicating basolateral expression of α-syn and TfR on RPE cells in vivo, this study reveals a novel function of α-syn in the uptake of Tf-Fe by the neuroretina. It is likely that retinal iron dyshomeostasis due to impaired or altered function of α-syn contributes to the visual symptoms associated with PD.

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“…Thus, at least under normal circumstances, increased iron importation could lead to improved management of ROS. This series of results and many other issues in iron homeostasis for the eye have been recently reviewed by the same group [18].…”

Section: Neural Tissue and Related Cell Typesmentioning

confidence: 99%

“…It will repeat information only where essential for understanding of a topic. New recent relevant reviews include coverage of iron acquisition and storage [8], impaired iron homeostasis in Parkinsonism [28], normal iron homeostasis from a molecular viewpoint [56], normal and pathological iron homeostasis in the eye [18], hereditary hemochromatosis [52], hepcidin's role as a regulator [36] and recycling of iron primarily by macrophage [2].…”

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confidence: 99%

Human iron transporters

Garrick

2010

Genes Nutr

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Human iron transporters manage iron carefully because tissues need iron for critical functions, but too much iron increases the risk of reactive oxygen species. Iron acquisition occurs in the duodenum via divalent metal transporter (DMT1) and ferroportin. Iron trafficking depends largely on the transferrin cycle. Nevertheless, nondigestive tissues have a variety of other iron transporters that may render DMT1 modestly redundant, and DMT1 levels exceed those needed for the just-mentioned tasks. This review begins to consider why and also describes advances after 2008 that begin to address this challenge.

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Iron metabolism in the eye: A review

Cited by 45 publications

References 168 publications

Iron importers Zip8 and Zip14 are expressed in retina and regulated by retinal iron levels

Iron importers Zip8 and Zip14 are expressed in retina and regulated by retinal iron levels

Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrin-bound iron: Implications for visual manifestations of Parkinson's disease

Human iron transporters

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