scholarly journals An improved structural model of the human iron exporter ferroportin. Insight into the role of pathogenic mutations in hereditary hemochromatosis type 4

2017 ◽  
Vol 13 (4) ◽  
Author(s):  
Valentina Tortosa ◽  
Maria Carmela Bonaccorsi di Patti ◽  
Valentina Brandi ◽  
Giovanni Musci ◽  
Fabio Polticelli
Keyword(s):  
Membrane Protein ◽  
Crystal Structures ◽  
Iron Homeostasis ◽  
Structural Model ◽  
Hereditary Hemochromatosis ◽  
Structural Models ◽  
Pivotal Role ◽  
Cellular Iron ◽  
Insight Into

AbstractFerroportin (Fpn) is a membrane protein representing the major cellular iron exporter, essential for metal translocation from cells into plasma. Despite its pivotal role in human iron homeostasis, many questions on Fpn structure and biology remain unanswered. In this work, we present two novel and more reliable structural models of human Fpn (hFpn; inward-facing and outward-facing conformations) obtained using as templates the recently solved crystal structures of a bacterial homologue of hFpn,

HFE Downregulates Iron Uptake From Transferrin and Induces Iron-Regulatory Protein Activity in Stably Transfected Cells

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3915-3921 ◽  
Author(s):  
H.D. Riedel ◽  
M.U. Muckenthaler ◽  
S.G. Gehrke ◽  
I. Mohr ◽  
K. Brennan ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Regulatory Protein ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Iron Regulatory Proteins ◽  
Cellular Iron

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder of iron metabolism. More than 80% of HH patients are homozygous for a point mutation in a major histocompatibility complex (MHC) class I type protein (HFE), which results in a lack of HFE expression on the cell surface. A previously identified interaction of HFE and the transferrin receptor suggests a possible regulatory role of HFE in cellular iron absorption. Using an HeLa cell line stably transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron uptake. We demonstrate that the overproduction of HFE results in decreased iron uptake from diferric transferrin. Moreover, HFE expression activates the key regulators of intracellular iron homeostasis, the iron-regulatory proteins (IRPs), implying that HFE can affect the intracellular “labile iron pool.” The increase in IRP activity is accompanied by the downregulation of the iron-storage protein, ferritin, and an upregulation of transferrin receptor levels. These findings are discussed in the context of the pathophysiology of HH and a possible role of iron-responsive element (IRE)-containing mRNAs.

HFE Downregulates Iron Uptake From Transferrin and Induces Iron-Regulatory Protein Activity in Stably Transfected Cells

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3915-3921 ◽  
Author(s):  
H.D. Riedel ◽  
M.U. Muckenthaler ◽  
S.G. Gehrke ◽  
I. Mohr ◽  
K. Brennan ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Regulatory Protein ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Iron Regulatory Proteins ◽  
Cellular Iron

Abstract Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder of iron metabolism. More than 80% of HH patients are homozygous for a point mutation in a major histocompatibility complex (MHC) class I type protein (HFE), which results in a lack of HFE expression on the cell surface. A previously identified interaction of HFE and the transferrin receptor suggests a possible regulatory role of HFE in cellular iron absorption. Using an HeLa cell line stably transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron uptake. We demonstrate that the overproduction of HFE results in decreased iron uptake from diferric transferrin. Moreover, HFE expression activates the key regulators of intracellular iron homeostasis, the iron-regulatory proteins (IRPs), implying that HFE can affect the intracellular “labile iron pool.” The increase in IRP activity is accompanied by the downregulation of the iron-storage protein, ferritin, and an upregulation of transferrin receptor levels. These findings are discussed in the context of the pathophysiology of HH and a possible role of iron-responsive element (IRE)-containing mRNAs.

scholarly journals GSK-3β manipulates ferroptosis sensitivity by dominating iron homeostasis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Lingjuan Wang ◽  
Sijin Ouyang ◽  
Bin Li ◽  
Hao Wu ◽  
Fengli Wang
Keyword(s):  
Iron Homeostasis ◽  
Lipid Peroxides ◽  
Iron Level ◽  
The Past ◽  
Cellular Iron ◽  
Regulatory Circuits ◽  
Positive Modulator ◽  
Gsk 3Β ◽  
Insight Into

AbstractFerroptosis is a newly characterized form of non-apoptotic-programmed cell death, which is driven by the lethal accumulation of iron-catalyzed lipid peroxides. Uncontrolled ferroptosis is implicated in the pathogenesis of a group of human diseases, while targeted induction of ferroptosis provides a potent therapeutic design for cancers. During the past decade, the fundamental regulatory circuits of ferroptosis have been identified. In this study, we show that the multifaceted Ser/Thr protein kinase GSK-3β acts as a positive modulator of the ferroptosis program. Pharmacological inhibition of GSK-3β by selective inhibitor LY2090314 or genetic KD of GSK-3β by shRNA potently promotes ferroptotic resistance. GSK-3β KD antagonizes the expression of iron metabolic components including DMT1, FTH1, and FTL, leading to the disruption of iron homeostasis and decline in intracellular labile free iron level. Taken together, our findings elaborate an indispensable role of GSK-3β in determining ferroptotic sensitivity by dominating cellular iron metabolism, which provides further insight into GSK-3β as a target for cancer chemotherapy.

The pivotal role of ferritin in cellular iron homeostasis

BioEssays ◽  
1988 ◽  
Vol 8 (4) ◽  
pp. 107-111 ◽  
Author(s):  
Elena Mattia ◽  
Jos van Renswoude
Keyword(s):  
Iron Homeostasis ◽  
Pivotal Role ◽  
Cellular Iron ◽  
Cellular Iron Homeostasis

The Zebrafish Hypochromic Mutant [iItalic]Shiraz[/iItalic] Encodes a Novel Mitochondrial Glutaredoxin That Establishes a Link between Heme and Fe/S Production.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 51-51
Author(s):  
Rebecca A. Wingert ◽  
Bruce Barut ◽  
Helen Foott ◽  
Paula Fraenkel ◽  
Kimberly Dooley ◽  
...  
Keyword(s):  
Positional Cloning ◽  
Iron Homeostasis ◽  
Rna Binding ◽  
Fetal Liver ◽  
Regulatory Protein ◽  
Cluster Assembly ◽  
Hemoglobin Synthesis ◽  
Cellular Iron ◽  
Hemoglobin Production

Abstract Iron is required in the mitochondria both to produce heme, which is used for hemoglobin synthesis, and to make iron-sulfur (Fe/S) clusters, which confer electron transfer or catalytic functions to proteins. Cellular iron utilization and Fe/S cluster production are thought to occur independently, yet the processes are coordinated through currently uncharacterized pathways. The shiraz (sir) zebrafish mutant manifests a hypochromic, microcytic anemia. Positional cloning of sir discovered a deletion at the locus that included the zebrafish orthologue to glutaredoxin 5 (grx5), a gene required in yeast for Fe/S cluster assembly. We found that grx5 is highly expressed in the developing blood and fetal liver of both zebrafish and mouse embryos. Antisense-mediated morpholino knockdown of grx5 prevented hemoglobin production, and overexpression of zebrafish, yeast, mouse, or human grx5 RNA in sir embryos completely rescued hemoglobin production, indicating that grx5 is the gene responsible for the sir phenotype. Expression of zebrafish grx5 was found to rescue Fe/S protein production in the yeast Δgrx5 strain, demonstrating that the role of grx5 in Fe/S cluster assembly is conserved among eukaryotes. The surprising finding that mutating a gene necessary for Fe/S cluster assembly caused a lack of hemoglobin synthesis suggested that we had discovered a connection between these pathways. In vertebrates, iron regulatory protein 1 (IRP1) acts as a sensor of intracellular iron levels and controls cellular iron homeostasis via posttranscriptional regulation of iron uptake, storage, and utilization genes. For instance, IRP1 binds to the 5′ iron response element (IRE) in the aminolevulinate synthase 2 (ALAS2) mRNA, blocking translation when cellular iron is low. However, when cellular iron is replete, IRP1 binds a Fe/S cluster and its RNA-binding activity is abolished. We hypothesized that the loss of Fe/S cluster assembly in sir would activate IRP1 and block ALAS2 synthesis, resulting in hypochromia. In support of this model, overexpression of ALAS2 RNA without the 5′ IRE rescued sir hypochromia, while overexpression of ALAS2 including the IRE did not facilitate rescue. Furthermore, antisense morpholino knockdowns of IRP1 caused rescue of hemoglobin synthesis in sir embryos. The combination of these data indicate that hemoglobin production in the differentiating red cell is monitored through Fe-S cluster assembly as a mechanism to gauge iron levels and accordingly direct heme synthesis. This finding illustrates a crucial role for the mitochondrial Fe/S cluster assembly machinery during hemoglobin production, and has broad implications for the role of such genes in human hypochromic anemias.

Physiology of iron transport and the hemochromatosis gene

2002 ◽  
Vol 282 (3) ◽  
pp. G403-G414 ◽  
Author(s):  
Antonello Pietrangelo
Keyword(s):  
Iron Homeostasis ◽  
Cell Damage ◽  
Hereditary Hemochromatosis ◽  
Hfe Gene ◽  
Cell Functions ◽  
Cellular Iron ◽  
Histocompatibility Complex ◽  
Biological Studies ◽  
Hemochromatosis Gene ◽  
Main Protein

Iron is essential for fundamental cell functions but is also a catalyst for chemical reactions involving free radical formation, potentially leading to oxidative stress and cell damage. Cellular iron levels are therefore carefully regulated to maintain an adequate substrate while also minimizing the pool of potentially toxic “free iron.” The main control of body iron homeostasis in higher organisms is placed in the duodenum, where dietary iron is absorbed, whereas no controlled means of eliminating unwanted iron have evolved in mammals. Hereditary hemochromatosis, the prototype of deregulated iron homeostasis in humans, is due to inappropriately increased iron absorption and is commonly associated to a mutated HFE gene. The HFE protein is homologous to major histocompatibility complex class I proteins but is not an iron carrier, whereas biochemical and cell biological studies have shown that the transferrin receptor, the main protein devoted to cellular uptake of transferrin iron, interacts with HFE. This review focuses on recent advances in iron research and presents a model of HFE function in iron metabolism.

scholarly journals Enhanced erythropoiesis in Hfe-KO mice indicates a role for Hfe in the modulation of erythroid iron homeostasis

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1379-1389 ◽  
Author(s):  
Pedro Ramos ◽  
Ella Guy ◽  
Nan Chen ◽  
Catia C. Proenca ◽  
Sara Gardenghi ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Dietary Iron ◽  
Erythroid Cells ◽  
Hepcidin Expression ◽  
Stress Erythropoiesis ◽  
Cellular Iron ◽  
Cellular Iron Uptake

Abstract In hereditary hemochromatosis, mutations in HFE lead to iron overload through abnormally low levels of hepcidin. In addition, HFE potentially modulates cellular iron uptake by interacting with transferrin receptor, a crucial protein during erythropoiesis. However, the role of HFE in this process was never explored. We hypothesize that HFE modulates erythropoiesis by affecting dietary iron absorption and erythroid iron intake. To investigate this, we used Hfe-KO mice in conditions of altered dietary iron and erythropoiesis. We show that Hfe-KO mice can overcome phlebotomy-induced anemia more rapidly than wild-type mice (even when iron loaded). Second, we evaluated mice combining the hemochromatosis and β-thalassemia phenotypes. Our results suggest that lack of Hfe is advantageous in conditions of increased erythropoietic activity because of augmented iron mobilization driven by deficient hepcidin response. Lastly, we demonstrate that Hfe is expressed in erythroid cells and impairs iron uptake, whereas its absence exclusively from the hematopoietic compartment is sufficient to accelerate recovery from phlebotomy. In summary, we demonstrate that Hfe influences erythropoiesis by 2 distinct mechanisms: limiting hepcidin expression under conditions of simultaneous iron overload and stress erythropoiesis, and impairing transferrin-bound iron uptake by erythroid cells. Moreover, our results provide novel suggestions to improve the treatment of hemochromatosis.

scholarly journals Role of Nanomedicine in Management and Prevention of COVID-19

2020 ◽  
Vol 2 ◽  
Author(s):  
Jitendra N. Wankar ◽  
Vivek K. Chaturvedi ◽  
Chandrashekhar Bohara ◽  
Mohan P. Singh ◽  
Raghvendra A. Bohara
Keyword(s):  
Side Effects ◽  
Severe Acute Respiratory Syndrome ◽  
Disease Outbreak ◽  
Target Site ◽  
Inorganic Materials ◽  
Pivotal Role ◽  
The World ◽  
Insight Into

COVID-19, or the Coronavirus disease 2019, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic. At the time of writing this (July 28, 2020), more than 17 million people have become affected and 0.7 million people have died across the world. Remdesivir has shown glimpses of insight into how to fight the virus, but as of yet remain far from victory. Nanotechnology has proven its role in medicine to deliver the drug at the target site with minimal side effects, particularly in the anticancer domain. Most specifically, a range of nanotechnology-based products, such as nanosilver, are currently on the market because they have demonstrated the potential to combat viruses. This article provides an overview of the role of nanomedicine, including polymeric and inorganic materials, and its future capabilities in the management of the disease outbreak. Taking all this into account, an attempt has been made to educate readers in the simplest way of the role of nanomedicine, which can play a pivotal role in the management of diseases.

scholarly journals Distinct effects of Q925 mutation on intracellular and extracellular Na+ and K+ binding to the Na+, K+-ATPase

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hang N. Nielsen ◽  
Kerri Spontarelli ◽  
Rikke Holm ◽  
Jens Peter Andersen ◽  
Anja P. Einholm ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Crystal Structures ◽  
Binding Sites ◽  
Functional Role ◽  
Transmembrane Helix ◽  
Binding Properties ◽  
Ion Translocation ◽  
Extracellular Side ◽  
Insight Into

Abstract Three Na+ sites are defined in the Na+-bound crystal structure of Na+, K+-ATPase. Sites I and II overlap with two K+ sites in the K+-bound structure, whereas site III is unique and Na+ specific. A glutamine in transmembrane helix M8 (Q925) appears from the crystal structures to coordinate Na+ at site III, but does not contribute to K+ coordination at sites I and II. Here we address the functional role of Q925 in the various conformational states of Na+, K+-ATPase by examining the mutants Q925A/G/E/N/L/I/Y. We characterized these mutants both enzymatically and electrophysiologically, thereby revealing their Na+ and K+ binding properties. Remarkably, Q925 substitutions had minor effects on Na+ binding from the intracellular side of the membrane – in fact, mutations Q925A and Q925G increased the apparent Na+ affinity – but caused dramatic reductions of the binding of K+ as well as Na+ from the extracellular side of the membrane. These results provide insight into the changes taking place in the Na+-binding sites, when they are transformed from intracellular- to extracellular-facing orientation in relation to the ion translocation process, and demonstrate the interaction between sites III and I and a possible gating function of Q925 in the release of Na+ at the extracellular side.

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