Expression and localization of duodenal cytochrome b in the rat hippocampus after kainate-induced excitotoxicity

Loke, Sau Yeen; Siddiqi, Nikhat J.; Alhomida, Abdullah S.; Kim, H.-C.; Ong, Wei Yi

doi:10.1016/j.neuroscience.2013.04.008

Cited by 10 publications

(8 citation statements)

References 49 publications

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“…Evidence shows that the uptake of Tf-Fe (also known as holo-Tf) by TfR1-mediated endocytosis from the blood into cerebral endothelial cells is no different in nature from its uptake into other cell types (Bradbury, 1997). This process includes several steps (Qian & Tang, 1995;Qian, Tang, & Wang, 1997): (i) binding of two holo-Tf molecules with the diametric TfR1 (McCarthy & Kosman, 2015); (ii) endocytosis of the holo-Tf-TfR1 complex which is clathrin dependent; (iii) acidification by the action of an H + -ATPase (Nelson & Harvey, 1999) and dissociation of Fe 3+ from Tf in the endosome; (iv) reduction of Fe 3+ to Fe 2+ in the endosome, likely by the ferrireductases duodenal cytochrome b (Dcytb) and six-transmembrane epithelial antigen of the prostate 2 (STEAP2) (Ohgami et al, 2005(Ohgami et al, , 2006De Domenico, Mcvey Ward, & Kaplan, 2008;Tulpule et al, 2010;McCarthy & Kosman, 2012Loke et al, 2013); (v) translocation of Fe 2+ across the endosomal membrane by a process mediated by divalent metal transporter 1 (DMT1/Nramp2/DCT1) (Fleming et al, 1997;Gunshin et al, 1997;Burdo et al, 2001;Siddappa et al, 2002;Rouault & Cooperman, 2006;Garrick, 2011;McCarthy & Kosman, 2012;Duck et al, 2017); (vi) mobilization of iron for metabolism, mostly transported into mitochondria via the inner membrane protein mitoferrin 1/solute carrier family 25, member 37 (Mfrn1/SLC25A37) (Shaw et al, Fig. 1.…”

Section: (1) Iron Transport Across the Luminal (Apical) Membrane Of Tmentioning

confidence: 99%

Brain iron transport

Qian

2019

Biological Reviews

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Brain iron is a crucial participant and regulator of normal physiological activity. However, excess iron is involved in the formation of free radicals, and has been associated with oxidative damage to neuronal and other brain cells. Abnormally high brain iron levels have been observed in various neurodegenerative diseases, including neurodegeneration with brain iron accumulation, Alzheimer's disease, Parkinson's disease and Huntington's disease. However, the key question of why iron levels increase in the relevant regions of the brain remains to be answered. A full understanding of the homeostatic mechanisms involved in brain iron transport and metabolism is therefore critical not only for elucidating the pathophysiological mechanisms responsible for excess iron accumulation in the brain but also for developing pharmacological interventions to disrupt the chain of pathological events occurring in these neurodegenerative diseases. Numerous studies have been conducted, but to date no effort to synthesize these studies and ideas into a systematic and coherent summary has been made, especially concerning iron transport across the luminal (apical) membrane of the capillary endothelium and the membranes of different brain cell types. Herein, we review key findings on brain iron transport, highlighting the mechanisms involved in iron transport across the luminal (apical) as well as the abluminal (basal) membrane of the blood–brain barrier, the blood–cerebrospinal fluid barrier, and iron uptake and release in neurons, oligodendrocytes, astrocytes and microglia within the brain. We offer suggestions for addressing the many important gaps in our understanding of this important topic, and provide new insights into the potential causes of abnormally increased iron levels in regions of the brain in neurodegenerative disorders.

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Section: (1) Iron Transport Across the Luminal (Apical) Membrane Of Tmentioning

confidence: 99%

Brain iron transport

Qian

2019

Biological Reviews

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“…The transcripts that encodes Dcytb has been identified in cultured astrocytes from rats and mice [46, 47]. In 2013, Dcytb protein was demonstrated in hippocampal astrocyte endfeet surrounding the BMVEC of rats, potentially providing a source of ferrireduction for BMVEC-released Fe III [48]. …”

Section: Proteins Involved In Bmvec Iron Uptakementioning

confidence: 99%

Iron transport across the blood–brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy

McCarthy

Kosman

2014

Cell. Mol. Life Sci.

113

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There are two barriers for iron entry into the brain: 1) the brain-cerebrospinal fluid (CSF) barrier and 2) the blood-brain barrier (BBB). Here, we review the literature on developmental iron accumulation by the brain, focusing on the transport of iron through the brain microvascular endothelial cells (BMVEC) of the BBB. We review the iron trafficking proteins which may be involved in the iron flux across BMVEC and discuss the plausible mechanisms of BMVEC iron uptake and efflux. We suggest a model for how BMVEC iron uptake and efflux are regulated and a mechanism by which the majority of iron is trafficked across the developing BBB under the direct guidance of neighboring astrocytes. Thus, we place brain iron uptake in the context of the neurovascular unit of the adult brain. Last, we propose that BMVEC iron is involved in the aggregation of amyloid-β peptides leading to the progression of cerebral amyloid angiopathy which often occurs prior to dementia and the onset of Alzheimer's disease.

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“…Dcytb shares 45-50% sequence homology with cytochrome b561, a member of the family of oxidoreductases that is involved in ascorbate-mediated transmembrane electron transport. Its expression has also been reported in the lungs 1;2 , human erythrocytes 3 and in the brain 4 . Dcytb functions as a reductase in the conversion of ferric to ferrous ion for apical membrane import 1 by the divalent metal transporter (DMT1).…”

Section: Introductionmentioning

confidence: 74%

Duodenal cytochrome b (Cybrd1) ferric reductase functional studies in cells

2017

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Dietary non-heme ferric iron is reduced by the ferric reductase enzyme, duodenal cytochrome b (Dcytb), before absorption by the divalent metal transporter 1 (DMT1). A single nucleotide polymorphism (SNP rs10455 mutant) that is located in the last exon of the Dcytb gene was reported in C282Y haemochromatosis HFE subjects. The present work therefore investigated the phenotype of this mutant Dcytb in Chinese hamster ovary (CHO) cells. These cultured cells were transfected with either wild type (WT) or the SNP vector plasmids of Dcytb. Ferric reductase assays were performed in Dcytb transgenic CHO cells using the ferrozine spectrophometric assay protocol. The Dcytb SNP rs10455 showed a gain-of-function capability since ferric reductase activity increased significantly (p < 0.01) in the transgenic cells. Varying ferric reductase activity was found when CHO cells were pretreated with modulators of Dcytb protein expression. Although ferric reductase in endogenous CHO cells increased with deferoxamine or CoCl, iron loading with ferric ammonium citrate (FAC) had the opposite effect. Taken together, the study reveals a gain-of-function phenotype for Dcytb rs10455 mutation that could be a putative modifier of colorectal cancer risk, with attendant variability in penetrance among human HFE C282Y homozygotes.

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Expression and localization of duodenal cytochrome b in the rat hippocampus after kainate-induced excitotoxicity

Cited by 10 publications

References 49 publications

Brain iron transport

Brain iron transport

Iron transport across the blood–brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy

Duodenal cytochrome b (Cybrd1) ferric reductase functional studies in cells

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