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Ferroportin and Ceruloplasmin: Structure and Function in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 34969

Special Issue Editors


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Guest Editor
Department of Biosciences and Territory, University of Molise, 86090 Pesche, Italy
Interests: iron homeostasis; ceruloplasmin; ferroportin; copper; metalloproteins; lactoferrin; inflammation; structural biology
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Guest Editor
Dipartimento di Scienze biochimiche ‘A. Rossi Fanelli’, Università degli Studi di Roma La Sapienza, Rome, Italy
Interests: iron; copper; multicopper oxidase; ceruloplasmin; ferroportin; lactoferrin; neurodegeneration; oxidative stress; yeast; membrane proteins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the last years, our understanding of the role of proteins involved in the handling of iron in health and disease had tremendously advanced  due to the efforts of many research groups around the world. Two proteins playing a key role in the cellular management of iron are ferroportin, the only known cellular iron exporter in mammals, and ceruloplasmin, a multifunctional enzyme with ferroxidase activity. A strong connection between ferroportin and ceruloplasmin was uncovered and they can be viewed as a system of functionally interacting partners. The importance of both proteins is underscored by the finding that mutations in each cause iron imbalance leading to pathological states, particularly severe in the case of aceruloplasminemia which belongs to the neurodegeneration with brain iron accumulation (NBIA) group.

This Special Issue of IJMS will focus on recent advances regarding different aspects of ferroportin and ceruloplasmin biology in health and disease: molecular structure and mechanism of action, regulation of expression, interactions with other proteins, exploitation as drug targets, and roles in other pathological states where iron status is altered (e.g., infection and inflammation, cancer, etc.). Original papers and review articles on these and related topics are welcome.

Dr. Giovanni Musci
Dr. Maria Carmela Bonaccorsi Di Patti
Guest Editors

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Keywords

  • ferroportin
  • ceruloplasmin
  • iron
  • copper
  • neurodegeneration

Published Papers (9 papers)

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Research

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12 pages, 1943 KiB  
Article
Heart Ferroportin Protein Content Is Regulated by Heart Iron Concentration and Systemic Hepcidin Expression
by Betty Berezovsky, Jana Frýdlová, Iuliia Gurieva, Daniel W. Rogalsky, Martin Vokurka and Jan Krijt
Int. J. Mol. Sci. 2022, 23(11), 5899; https://doi.org/10.3390/ijms23115899 - 24 May 2022
Cited by 6 | Viewed by 2312
Abstract
The purpose of the study was to investigate the expression of ferroportin protein following treatments that affect systemic hepcidin. Administration of erythropoietin to C57BL/6J mice decreased systemic hepcidin expression; it also increased heart ferroportin protein content, determined by immunoblot in the membrane fraction, [...] Read more.
The purpose of the study was to investigate the expression of ferroportin protein following treatments that affect systemic hepcidin. Administration of erythropoietin to C57BL/6J mice decreased systemic hepcidin expression; it also increased heart ferroportin protein content, determined by immunoblot in the membrane fraction, to approximately 200% of control values. This increase in heart ferroportin protein is very probably caused by a decrease in systemic hepcidin expression, in accordance with the classical regulation of ferroportin by hepcidin. However, the control of heart ferroportin protein by systemic hepcidin could apparently be overridden by changes in heart non-heme iron content since injection of ferric carboxymaltose to mice at 300 mg Fe/kg resulted in an increase in liver hepcidin expression, heart non-heme iron content, and also a threefold increase in heart ferroportin protein content. In a separate experiment, feeding an iron-deficient diet to young Wistar rats dramatically decreased liver hepcidin expression, while heart non-heme iron content and heart ferroportin protein content decreased to 50% of controls. It is, therefore, suggested that heart ferroportin protein is regulated primarily by the iron regulatory protein/iron-responsive element system and that the regulation of heart ferroportin by the hepcidin-ferroportin axis plays a secondary role. Full article
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16 pages, 962 KiB  
Article
Ceruloplasmin as Redox Marker Related to Heart Failure Severity
by Elżbieta Lazar-Poloczek, Ewa Romuk, Piotr Rozentryt, Sylwia Duda, Mariusz Gąsior and Celina Wojciechowska
Int. J. Mol. Sci. 2021, 22(18), 10074; https://doi.org/10.3390/ijms221810074 - 17 Sep 2021
Cited by 5 | Viewed by 2197
Abstract
This study examined ceruloplasmin levels in patients with HFrEF, depending on cardiopulmonary exercise testing (CPET) parameters; a correlation was found between ceruloplasmin (CER) and iron and hepatic status, inflammatory and redox biomarkers. A group of 552 patients was divided according to Weber’s classification: [...] Read more.
This study examined ceruloplasmin levels in patients with HFrEF, depending on cardiopulmonary exercise testing (CPET) parameters; a correlation was found between ceruloplasmin (CER) and iron and hepatic status, inflammatory and redox biomarkers. A group of 552 patients was divided according to Weber’s classification: there were 72 (13%) patients in class A (peak VO2 > 20 mL/kg/min), 116 (21%) patients in class B (peak VO2 16–20 mL/kg/min), 276 (50%) patients in class C (peak VO2 10–15.9 mL/kg/min) and 88 (16%) patients in class D (peak VO2 < 10 mL/kg/min). A higher concentration of CER was found in patients with peak VO2 < 16 mL/kg/min and VE/CO2 slope > 45 compared to patients with VE/CO2 slope < 45 (escectively CER 30.6 mg/dL and 27.5 mg/dL). A significantly positive correlation was found between ceruloplasmin and NYHA class, RV diameter, NT-proBNP, uric acid, total protein, fibrinogen and hepatic enzymes. CER was positively correlated with both total oxidant status (TOS), total antioxidant capacity (TAC) and malondialdehyde. A model constructed to predict CER concentration indicated that TOS, malondialdehyde and alkaline phosphatase were independent predictive variables (R2 0.14, p < 0.001). CER as a continuous variable was an independent predictor of pVO2 ≤ 12 mL/kg/min after adjustment for sex, age and BMI. These results provide the basis of a new classification to encourage the determination of CER as a useful biomarker in HFrEF. Full article
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10 pages, 1134 KiB  
Article
Production of Recombinant Human Ceruloplasmin: Improvements and Perspectives
by Maria Carmela Bonaccorsi di Patti, Antimo Cutone, Marek Nemčovič, Zuzana Pakanová, Peter Baráth and Giovanni Musci
Int. J. Mol. Sci. 2021, 22(15), 8228; https://doi.org/10.3390/ijms22158228 - 30 Jul 2021
Cited by 1 | Viewed by 2280
Abstract
The ferroxidase ceruloplasmin (CP) plays a crucial role in iron homeostasis in vertebrates together with the iron exporter ferroportin. Mutations in the CP gene give rise to aceruloplasminemia, a rare neurodegenerative disease for which no cure is available. Many aspects of the (patho)physiology [...] Read more.
The ferroxidase ceruloplasmin (CP) plays a crucial role in iron homeostasis in vertebrates together with the iron exporter ferroportin. Mutations in the CP gene give rise to aceruloplasminemia, a rare neurodegenerative disease for which no cure is available. Many aspects of the (patho)physiology of CP are still unclear and would benefit from the availability of recombinant protein for structural and functional studies. Furthermore, recombinant CP could be evaluated for enzyme replacement therapy for the treatment of aceruloplasminemia. We report the production and preliminary characterization of high-quality recombinant human CP in glycoengineered Pichia pastoris SuperMan5. A modified yeast strain lacking the endogenous ferroxidase has been generated and employed as host for heterologous expression of the secreted isoform of human CP. Highly pure biologically active protein has been obtained by an improved two-step purification procedure. Glycan analysis indicates that predominant glycoforms HexNAc2Hex8 and HexNAc2Hex11 are found at Asn119, Asn378, and Asn743, three of the canonical four N-glycosylation sites of human CP. The availability of high-quality recombinant human CP represents a significant advancement in the field of CP biology. However, productivity needs to be increased and further careful glycoengineering of the SM5 strain is mandatory in order to evaluate the possible therapeutic use of the recombinant protein for enzyme replacement therapy of aceruloplasminemia patients. Full article
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12 pages, 5735 KiB  
Article
Insights into the Role of the Discontinuous TM7 Helix of Human Ferroportin through the Prism of the Asp325 Residue
by Marlène Le Tertre, Ahmad Elbahnsi, Chandran Ka, Isabelle Callebaut and Gérald Le Gac
Int. J. Mol. Sci. 2021, 22(12), 6412; https://doi.org/10.3390/ijms22126412 - 15 Jun 2021
Viewed by 1816
Abstract
The negatively charged Asp325 residue has proved to be essential for iron export by human (HsFPN1) and primate Philippine tarsier (TsFpn) ferroportin, but its exact role during the iron transport cycle is still to be elucidated. It has been posited as being functionally [...] Read more.
The negatively charged Asp325 residue has proved to be essential for iron export by human (HsFPN1) and primate Philippine tarsier (TsFpn) ferroportin, but its exact role during the iron transport cycle is still to be elucidated. It has been posited as being functionally equivalent to the metal ion-coordinating residue His261 in the C-lobe of the bacterial homolog BbFpn, but the two residues arise in different sequence motifs of the discontinuous TM7 transmembrane helix. Furthermore, BbFpn is not subject to extracellular regulation, contrary to its mammalian orthologues which are downregulated by hepcidin. To get further insight into the molecular mechanisms related to iron export in mammals in which Asp325 is involved, we investigated the behavior of the Asp325Ala, Asp325His, and Asp325Asn mutants in transiently transfected HEK293T cells, and performed a comparative structural analysis. Our biochemical studies clearly distinguished between the Asp325Ala and Asp325His mutants, which result in a dramatic decrease in plasma membrane expression of FPN1, and the Asp325Asn mutant, which alters iron egress without affecting protein localization. Analysis of the 3D structures of HsFPN1 and TsFpn in the outward-facing (OF) state indicated that Asp325 does not interact directly with metal ions but is involved in the modulation of Cys326 metal-binding capacity. Moreover, models of the architecture of mammalian proteins in the inward-facing (IF) state suggested that Asp325 may form an inter-lobe salt-bridge with Arg40 (TM1) when not interacting with Cys326. These findings allow to suggest that Asp325 may be important for fine-tuning iron recognition in the C-lobe, as well as for local structural changes during the IF-to-OF transition at the extracellular gate level. Inability to form a salt-bridge between TM1 and TM7b during iron translocation could lead to protein instability, as shown by the Asp325Ala and Asp325His mutants. Full article
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11 pages, 4184 KiB  
Article
The Oral Ferroportin Inhibitor VIT-2763 Improves Erythropoiesis without Interfering with Iron Chelation Therapy in a Mouse Model of β-Thalassemia
by Naja Nyffenegger, Anna Flace, Cédric Doucerain, Franz Dürrenberger and Vania Manolova
Int. J. Mol. Sci. 2021, 22(2), 873; https://doi.org/10.3390/ijms22020873 - 16 Jan 2021
Cited by 13 | Viewed by 2773
Abstract
In β-thalassemia, ineffective erythropoiesis leads to anemia and systemic iron overload. The management of iron overload by chelation therapy is a standard of care. However, iron chelation does not improve the ineffective erythropoiesis. We recently showed that the oral ferroportin inhibitor VIT-2763 ameliorates [...] Read more.
In β-thalassemia, ineffective erythropoiesis leads to anemia and systemic iron overload. The management of iron overload by chelation therapy is a standard of care. However, iron chelation does not improve the ineffective erythropoiesis. We recently showed that the oral ferroportin inhibitor VIT-2763 ameliorates anemia and erythropoiesis in the Hbbth3/+ mouse model of β-thalassemia. In this study, we investigated whether concurrent use of the iron chelator deferasirox (DFX) and the ferroportin inhibitor VIT-2763 causes any pharmacodynamic interactions in the Hbbth3/+ mouse model of β-thalassemia. Mice were treated with VIT-2763 or DFX alone or with the combination of both drugs once daily for three weeks. VIT-2763 alone or in combination with DFX improved anemia and erythropoiesis. VIT-2763 alone decreased serum iron and transferrin saturation (TSAT) but was not able to reduce the liver iron concentration. While DFX alone had no effect on TSAT and erythropoiesis, it significantly reduced the liver iron concentration alone and in the presence of VIT-2763. Our results clearly show that VIT-2763 does not interfere with the iron chelation efficacy of DFX. Furthermore, VIT-2763 retains its beneficial effects on improving ineffective erythropoiesis when combined with DFX in the Hbbth3/+ mouse model. In conclusion, co-administration of the oral ferroportin inhibitor VIT-2763 and the iron chelator DFX is feasible and might offer an opportunity to improve both ineffective erythropoiesis and iron overload in β-thalassemia. Full article
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13 pages, 3502 KiB  
Article
Dynamical Behavior of the Human Ferroportin Homologue from Bdellovibrio bacteriovorus: Insight into the Ligand Recognition Mechanism
by Valentina Tortosa, Maria Carmela Bonaccorsi di Patti, Federico Iacovelli, Andrea Pasquadibisceglie, Mattia Falconi, Giovanni Musci and Fabio Polticelli
Int. J. Mol. Sci. 2020, 21(18), 6785; https://doi.org/10.3390/ijms21186785 - 16 Sep 2020
Cited by 4 | Viewed by 2017
Abstract
Members of the major facilitator superfamily of transporters (MFS) play an essential role in many physiological processes such as development, neurotransmission, and signaling. Aberrant functions of MFS proteins are associated with several diseases, including cancer, schizophrenia, epilepsy, amyotrophic lateral sclerosis and Alzheimer’s disease. [...] Read more.
Members of the major facilitator superfamily of transporters (MFS) play an essential role in many physiological processes such as development, neurotransmission, and signaling. Aberrant functions of MFS proteins are associated with several diseases, including cancer, schizophrenia, epilepsy, amyotrophic lateral sclerosis and Alzheimer’s disease. MFS transporters are also involved in multidrug resistance in bacteria and fungi. The structures of most MFS members, especially those of members with significant physiological relevance, are yet to be solved. The lack of structural and functional information impedes our detailed understanding, and thus the pharmacological targeting, of these transporters. To improve our knowledge on the mechanistic principles governing the function of MSF members, molecular dynamics (MD) simulations were performed on the inward-facing and outward-facing crystal structures of the human ferroportin homologue from the Gram-negative bacterium Bdellovibrio bacteriovorus (BdFpn). Several simulations with an excess of iron ions were also performed to explore the relationship between the protein’s dynamics and the ligand recognition mechanism. The results reinforce the existence of the alternating-access mechanism already described for other MFS members. In addition, the reorganization of salt bridges, some of which are conserved in several MFS members, appears to be a key molecular event facilitating the conformational change of the transporter. Full article
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Review

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13 pages, 1590 KiB  
Review
Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis
by Elizabeta Nemeth and Tomas Ganz
Int. J. Mol. Sci. 2021, 22(12), 6493; https://doi.org/10.3390/ijms22126493 - 17 Jun 2021
Cited by 203 | Viewed by 13085
Abstract
Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the stability of iron concentration in plasma and extracellular fluid, and the total body iron content are maintained by the [...] Read more.
Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the stability of iron concentration in plasma and extracellular fluid, and the total body iron content are maintained by the interaction of the iron-regulatory peptide hormone hepcidin with its receptor and cellular iron exporter ferroportin (SLC40a1). Ferroportin exports iron from duodenal enterocytes that absorb dietary iron, from iron-recycling macrophages in the spleen and the liver, and from iron-storing hepatocytes. Hepcidin blocks iron export through ferroportin, causing hypoferremia. During iron deficiency or after hemorrhage, hepcidin decreases to allow iron delivery to plasma through ferroportin, thus promoting compensatory erythropoiesis. As a host defense mediator, hepcidin increases in response to infection and inflammation, blocking iron delivery through ferroportin to blood plasma, thus limiting iron availability to invading microbes. Genetic diseases that decrease hepcidin synthesis or disrupt hepcidin binding to ferroportin cause the iron overload disorder hereditary hemochromatosis. The opposite phenotype, iron restriction or iron deficiency, can result from genetic or inflammatory overproduction of hepcidin. Full article
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15 pages, 881 KiB  
Review
Iron Availability in Tissue Microenvironment: The Key Role of Ferroportin
by Elena Gammella, Margherita Correnti, Gaetano Cairo and Stefania Recalcati
Int. J. Mol. Sci. 2021, 22(6), 2986; https://doi.org/10.3390/ijms22062986 - 15 Mar 2021
Cited by 11 | Viewed by 3623
Abstract
Body iron levels are regulated by hepcidin, a liver-derived peptide that exerts its function by controlling the presence of ferroportin (FPN), the sole cellular iron exporter, on the cell surface. Hepcidin binding leads to FPN internalization and degradation, thereby inhibiting iron release, in [...] Read more.
Body iron levels are regulated by hepcidin, a liver-derived peptide that exerts its function by controlling the presence of ferroportin (FPN), the sole cellular iron exporter, on the cell surface. Hepcidin binding leads to FPN internalization and degradation, thereby inhibiting iron release, in particular from iron-absorbing duodenal cells and macrophages involved in iron recycling. Disruption in this regulatory mechanism results in a variety of disorders associated with iron-deficiency or overload. In recent years, increasing evidence has emerged to indicate that, in addition to its role in systemic iron metabolism, FPN may play an important function in local iron control, such that its dysregulation may lead to tissue damage despite unaltered systemic iron homeostasis. In this review, we focus on recent discoveries to discuss the role of FPN-mediated iron export in the microenvironment under both physiological and pathological conditions. Full article
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12 pages, 1322 KiB  
Review
Ceruloplasmin Deamidation in Neurodegeneration: From Loss to Gain of Function
by Alan Zanardi and Massimo Alessio
Int. J. Mol. Sci. 2021, 22(2), 663; https://doi.org/10.3390/ijms22020663 - 11 Jan 2021
Cited by 13 | Viewed by 3338
Abstract
Neurodegenerative disorders can induce modifications of several proteins; one of which is ceruloplasmin (Cp), a ferroxidase enzyme found modified in the cerebrospinal fluid (CSF) of neurodegenerative diseases patients. Cp modifications are caused by the oxidation induced by the pathological environment and are usually [...] Read more.
Neurodegenerative disorders can induce modifications of several proteins; one of which is ceruloplasmin (Cp), a ferroxidase enzyme found modified in the cerebrospinal fluid (CSF) of neurodegenerative diseases patients. Cp modifications are caused by the oxidation induced by the pathological environment and are usually associated with activity loss. Together with oxidation, deamidation of Cp was found in the CSF from Alzheimer’s and Parkinson’s disease patients. Protein deamidation is a process characterized by asparagine residues conversion in either aspartate or isoaspartate, depending on protein sequence/structure and cellular environment. Cp deamidation occurs at two Asparagine-Glycine-Arginine (NGR)-motifs which, once deamidated to isoAspartate-Glycine-Arginine (isoDGR), bind integrins, a family of receptors mediating cell adhesion. Therefore, on the one hand, Cp modifications lead to loss of enzymatic activity, while on the other hand, these alterations confer gain of function to Cp. In fact, deamidated Cp binds to integrins and triggers intracellular signaling on choroid plexus epithelial cells, changing cell functioning. Working in concert with the oxidative environment, Cp deamidation could reach different target cells in the brain, altering their physiology and causing detrimental effects, which might contribute to the pathological mechanism. Full article
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