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Szymulewska-Konopko K, Reszeć-Giełażyn J, Małeczek M. Ferritin as an Effective Prognostic Factor and Potential Cancer Biomarker. Curr Issues Mol Biol 2025; 47:60. [PMID: 39852175 PMCID: PMC11763953 DOI: 10.3390/cimb47010060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/05/2025] [Accepted: 01/13/2025] [Indexed: 01/26/2025] Open
Abstract
Ferritin is found in all cells of the body, serving as a reservoir of iron and protecting against damage to the molecules that make up cellular structures. It has emerged as a biomarker not only for iron-related disorders but also for inflammatory diseases and conditions in which inflammation plays a key role, including cancer, neurodegeneration, and infection. Oxidative stress, which can cause cellular damage, is induced by reactive oxygen species generated during the Fenton reaction, activating signaling pathways associated with tumor growth and proliferation. This review primarily emphasizes basic studies on the identification and function of ferritin, its essential role in iron metabolism, its involvement in inflammatory diseases, and its potential as an important prognostic factor and biomarker for cancer detection.
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Affiliation(s)
| | - Joanna Reszeć-Giełażyn
- Department of Medical Pathomorphology, Medical University of Bialystok, 15-089 Białystok, Poland; (K.S.-K.); (M.M.)
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2
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Arosio P, Cairo G, Bou-Abdallah F. A Brief History of Ferritin, an Ancient and Versatile Protein. Int J Mol Sci 2024; 26:206. [PMID: 39796064 PMCID: PMC11719527 DOI: 10.3390/ijms26010206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 12/26/2024] [Accepted: 12/27/2024] [Indexed: 01/13/2025] Open
Abstract
Ferritin, a highly conserved iron storage protein, is among the earliest proteins that have been purified, named, and characterized due to its unique properties that continue to captivate researchers. Ferritin is composed of 24 subunits that form an almost spherical shell delimiting a cavity where thousands of iron atoms can be stored in a nontoxic ferric form, thereby preventing cytosolic iron from catalyzing oxidative stress. Mitochondrial and extracellular ferritin have also been described and characterized, with the latter being associated with several signaling functions. In addition, serum ferritin serves as a reliable indicator of both iron stores and inflammatory conditions. First identified and purified through crystallization in 1937, ferritin has since drawn significant attention for its critical role in iron metabolism and regulation. Its unique structural features have recently been exploited for many diverse biological and technological applications. To date, more than 40,000 publications have explored this remarkable protein. Here, we present a historical overview, tracing its journey from discovery to current applications and highlighting the evolution of biochemical techniques developed for its structure-function characterization over the past eight decades.
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Affiliation(s)
- Paolo Arosio
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Gaetano Cairo
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy;
| | - Fadi Bou-Abdallah
- Department of Chemistry, State University of New York at Potsdam, Potsdam, NY 13676, USA;
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3
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Nyvlt P, Schuster FS, Ihlow J, Heeren P, Spies C, Hiesgen J, Schenk T, von Brünneck AC, Westermann J, Brunkhorst FM, La Rosée P, Janka G, Lachmann C, Lachmann G. Value of hemophagocytosis in the diagnosis of hemophagocytic lymphohistiocytosis in critically ill patients. Eur J Haematol 2024; 112:917-926. [PMID: 38368850 DOI: 10.1111/ejh.14185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/24/2024] [Accepted: 01/25/2024] [Indexed: 02/20/2024]
Abstract
BACKGROUND Ferritin is an established biomarker in the diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH), which is diagnosed by the HLH-2004 criteria. Among these criteria, detection of hemophagocytosis through invasive procedures may delay early life saving treatment. Our aim was to investigate the value of hemophagocytosis in diagnosing HLH in critically ill patients. METHODS In this secondary analysis of a retrospective observational study, we included all patients aged ≥18 years and admitted to any adult ICU at Charité-Universitätsmedizin Berlin between January 2006 and August 2018, who had hyperferritinemia (≥500 μg/L) and underwent bone marrow biopsy during their ICU course. RESULTS Two hundred fifty-two patients were included, of whom 31 (12.3%) showed hemophagocytosis. In multivariable logistic regression analysis, maximum ferritin was independently associated with hemophagocytosis. By removing hemophagocytosis from HLH-2004 criteria and HScore, prediction accuracy for HLH diagnosis was only marginally decreased compared to the original scores. CONCLUSIONS Our results strengthen the diagnostic value of ferritin and underline the importance of considering HLH diagnosis in patients with high ferritin but only four fulfilled HLH-2004 criteria, when hemophagocytosis was not assessed or not detectable. Proof of hemophagocytosis is not required for a reliable HLH diagnosis.
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Affiliation(s)
- Peter Nyvlt
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine (CCM, CVK), Berlin, Germany
| | - Friederike S Schuster
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine (CCM, CVK), Berlin, Germany
| | - Jana Ihlow
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Berlin, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Patrick Heeren
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine (CCM, CVK), Berlin, Germany
| | - Claudia Spies
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine (CCM, CVK), Berlin, Germany
| | - Josephine Hiesgen
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine (CCM, CVK), Berlin, Germany
| | - Thomas Schenk
- Department of Hematology and Oncology, Universitätsklinikum Jena, Jena, Germany
| | - Ann-Christin von Brünneck
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Berlin, Germany
| | - Jörg Westermann
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumorimmunology, Berlin, Germany
| | - Frank M Brunkhorst
- Center for Clinical Studies, Department of Anesthesiology and Intensive Care Medicine, Universitätsklinikum Jena, Jena, Germany
| | - Paul La Rosée
- Klinik für Innere Medizin II, Schwarzwald-Baar-Klinikum, Villingen-Schwenningen, Germany
| | - Gritta Janka
- Clinic of Pediatric Hematology and Oncology, University Medical Center Eppendorf, Hamburg, Germany
| | - Cornelia Lachmann
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine (CCM, CVK), Berlin, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Gunnar Lachmann
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine (CCM, CVK), Berlin, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany
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4
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Srivastava AK, Reutovich AA, Hunter NJ, Arosio P, Bou-Abdallah F. Ferritin microheterogeneity, subunit composition, functional, and physiological implications. Sci Rep 2023; 13:19862. [PMID: 37963965 PMCID: PMC10646083 DOI: 10.1038/s41598-023-46880-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 11/06/2023] [Indexed: 11/16/2023] Open
Abstract
Ferritin is a ubiquitous intracellular iron storage protein that plays a crucial role in iron homeostasis. Animal tissue ferritins consist of multiple isoforms (or isoferritins) with different proportions of H and L subunits that contribute to their structural and compositional heterogeneity, and thus physiological functions. Using size exclusion and anion exchange chromatography, capillary isoelectric focusing (cIEF), and SDS-capillary gel electrophoresis (SDS-CGE), we reveal for the first time a significant variation in ferritin subunit composition and isoelectric points, in both recombinant and native ferritins extracted from animal organs. Our results indicate that subunits composition is the main determinant of the mean pI of recombinant ferritin heteropolymers, and that ferritin microheterogeneity is a common property of both natural and recombinant proteins and appears to be an intrinsic feature of the cellular machinery during ferritin expression, regulation, post-translational modifications, and post-subunits assembly. The functional significance and physiological implications of ferritin heterogeneity in terms of iron metabolism, response to oxidative stress, tissue-specific functions, and pathological processes are discussed.
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Affiliation(s)
- Ayush K Srivastava
- Department of Chemistry, State University of New York, Potsdam, NY, 13676, USA
| | | | - Nathan J Hunter
- Department of Chemistry, State University of New York, Potsdam, NY, 13676, USA
| | - Paolo Arosio
- Department of Molecular and Translational Medicine, University of Brescia, 25121, Brescia, Italy
| | - Fadi Bou-Abdallah
- Department of Chemistry, State University of New York, Potsdam, NY, 13676, USA.
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5
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Shesh BP, Connor JR. A novel view of ferritin in cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188917. [PMID: 37209958 PMCID: PMC10330744 DOI: 10.1016/j.bbcan.2023.188917] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/13/2023] [Accepted: 05/13/2023] [Indexed: 05/22/2023]
Abstract
Since its discovery more than 85 years ago, ferritin has principally been known as an iron storage protein. However, new roles, beyond iron storage, are being uncovered. Novel processes involving ferritin such as ferritinophagy and ferroptosis and as a cellular iron delivery protein not only expand our thinking on the range of contributions of this protein but present an opportunity to target these pathways in cancers. The key question we focus on within this review is whether ferritin modulation represents a useful approach for treating cancers. We discussed novel functions and processes of this protein in cancers. We are not limiting this review to cell intrinsic modulation of ferritin in cancers, but also focus on its utility in the trojan horse approach in cancer therapeutics. The novel functions of ferritin as discussed herein realize the multiple roles of ferritin in cell biology that can be probed for therapeutic opportunities and further research.
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Affiliation(s)
| | - James R Connor
- Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA, USA.
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6
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Gehrer CM, Mitterstiller AM, Grubwieser P, Meyron-Holtz EG, Weiss G, Nairz M. Advances in Ferritin Physiology and Possible Implications in Bacterial Infection. Int J Mol Sci 2023; 24:4659. [PMID: 36902088 PMCID: PMC10003477 DOI: 10.3390/ijms24054659] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/17/2023] [Accepted: 02/25/2023] [Indexed: 03/04/2023] Open
Abstract
Due to its advantageous redox properties, iron plays an important role in the metabolism of nearly all life. However, these properties are not only a boon but also the bane of such life forms. Since labile iron results in the generation of reactive oxygen species by Fenton chemistry, iron is stored in a relatively safe form inside of ferritin. Despite the fact that the iron storage protein ferritin has been extensively researched, many of its physiological functions are hitherto unresolved. However, research regarding ferritin's functions is gaining momentum. For example, recent major discoveries on its secretion and distribution mechanisms have been made as well as the paradigm-changing finding of intracellular compartmentalization of ferritin via interaction with nuclear receptor coactivator 4 (NCOA4). In this review, we discuss established knowledge as well as these new findings and the implications they may have for host-pathogen interaction during bacterial infection.
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Affiliation(s)
- Clemens M. Gehrer
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Anna-Maria Mitterstiller
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Philipp Grubwieser
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Esther G. Meyron-Holtz
- Laboratory of Molecular Nutrition, Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel
| | - Günter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Manfred Nairz
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, 6020 Innsbruck, Austria
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7
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CD63 is Regulated by Iron via the IRE-IRP System and is Important for Ferritin Secretion by Extracellular Vesicles. Blood 2021; 138:1490-1503. [PMID: 34265052 PMCID: PMC8667049 DOI: 10.1182/blood.2021010995] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 06/24/2021] [Indexed: 01/18/2023] Open
Abstract
CD63 is involved in EV secretion from cells and is shown herein to be regulated by iron via the IRE-IRP system. Iron-loading increased secretion of CD63+ EVs containing iron-loaded ferritin. Extracellular vesicles (EVs) transfer functional molecules between cells. CD63 is a widely recognized EV marker that contributes to EV secretion from cells. However, the regulation of its expression remains largely unknown. Ferritin is a cellular iron storage protein that can also be secreted by the exosome pathway, and serum ferritin levels classically reflect body iron stores. Iron metabolism–associated proteins such as ferritin are intricately regulated by cellular iron levels via the iron responsive element-iron regulatory protein (IRE-IRP) system. Herein, we present a novel mechanism demonstrating that the expression of the EV-associated protein CD63 is under the regulation of the IRE-IRP system. We discovered a canonical IRE in the 5′ untranslated region of CD63 messenger RNA that is responsible for regulating its expression in response to increased iron. Cellular iron loading caused a marked increase in CD63 expression and the secretion of CD63+ EVs from cells, which were shown to contain ferritin-H and ferritin-L. Our results demonstrate that under iron loading, intracellular ferritin is transferred via nuclear receptor coactivator 4 (NCOA4) to CD63+ EVs that are then secreted. Such iron-regulated secretion of the major iron storage protein ferritin via CD63+ EVs, is significant for understanding the local cell-to-cell exchange of ferritin and iron.
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8
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Plays M, Müller S, Rodriguez R. Chemistry and biology of ferritin. Metallomics 2021; 13:6244244. [PMID: 33881539 PMCID: PMC8083198 DOI: 10.1093/mtomcs/mfab021] [Citation(s) in RCA: 119] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 04/09/2021] [Indexed: 02/07/2023]
Abstract
Iron is an essential element required by cells and has been described as a key player in ferroptosis. Ferritin operates as a fundamental iron storage protein in cells forming multimeric assemblies with crystalline iron cores. We discuss the latest findings on ferritin structure and activity and its link to cell metabolism and ferroptosis. The chemistry of iron, including its oxidation states, is important for its biological functions, its reactivity, and the biology of ferritin. Ferritin can be localized in different cellular compartments and secreted by cells with a variety of functions depending on its spatial context. Here, we discuss how cellular ferritin localization is tightly linked to its function in a tissue-specific manner, and how impairment of iron homeostasis is implicated in diseases, including cancer and coronavirus disease 2019. Ferritin is a potential biomarker and we discuss latest research where it has been employed for imaging purposes and drug delivery.
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Affiliation(s)
- Marina Plays
- Chemical Biology of Cancer Laboratory, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.,Centre national de la recherche scientifique UMR 3666, Paris, France.,Institut national de la santé et de la recherche médicale U1143, Paris, France.,PSL Université Paris, Paris, France
| | - Sebastian Müller
- Chemical Biology of Cancer Laboratory, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.,Centre national de la recherche scientifique UMR 3666, Paris, France.,Institut national de la santé et de la recherche médicale U1143, Paris, France.,PSL Université Paris, Paris, France
| | - Raphaël Rodriguez
- Chemical Biology of Cancer Laboratory, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.,Centre national de la recherche scientifique UMR 3666, Paris, France.,Institut national de la santé et de la recherche médicale U1143, Paris, France.,PSL Université Paris, Paris, France
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9
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Hyperferritinemia-A Clinical Overview. J Clin Med 2021; 10:jcm10092008. [PMID: 34067164 PMCID: PMC8125175 DOI: 10.3390/jcm10092008] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/03/2021] [Accepted: 05/05/2021] [Indexed: 02/07/2023] Open
Abstract
Ferritin is one of the most frequently requested laboratory tests in primary and secondary care, and levels often deviate from reference ranges. Serving as an indirect marker for total body iron stores, low ferritin is highly specific for iron deficiency. Hyperferritinemia is, however, a non-specific finding, which is frequently overlooked in general practice. In routine medical practice, only 10% of cases are related to an iron overload, whilst the rest is seen as a result of acute phase reactions and reactive increases in ferritin due to underlying conditions. Differentiation of the presence or absence of an associated iron overload upon hyperferritinemia is essential, although often proves to be complex. In this review, we have performed a review of a selection of the literature based on the authors’ own experiences and assessments in accordance with international recommendations and guidelines. We address the biology, etiology, and epidemiology of hyperferritinemia. Finally, an algorithm for the diagnostic workup and management of hyperferritinemia is proposed, and general principles regarding the treatment of iron overload are discussed.
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10
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Grant ES, Clucas DB, McColl G, Hall LT, Simpson DA. Re-examining ferritin-bound iron: current and developing clinical tools. Clin Chem Lab Med 2020; 59:459-471. [PMID: 33090965 DOI: 10.1515/cclm-2020-1095] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 10/01/2020] [Indexed: 12/11/2022]
Abstract
Iron is a highly important metal ion cofactor within the human body, necessary for haemoglobin synthesis, and required by a wide range of enzymes for essential metabolic processes. Iron deficiency and overload both pose significant health concerns and are relatively common world-wide health hazards. Effective measurement of total iron stores is a primary tool for both identifying abnormal iron levels and tracking changes in clinical settings. Population based data is also essential for tracking nutritional trends. This review article provides an overview of the strengths and limitations associated with current techniques for diagnosing iron status, which sets a basis to discuss the potential of a new serum marker - ferritin-bound iron - and the improvement it could offer to iron assessment.
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Affiliation(s)
- Erin S Grant
- School of Physics, University of Melbourne, Parkville, VIC, Australia
| | - Danielle B Clucas
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.,Diagnostic Haematology, The Royal Melbourne Hospital, Parkville, VIC, Australia
| | - Gawain McColl
- Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health and the University of Melbourne, Parkville, VIC, Australia
| | - Liam T Hall
- School of Physics, University of Melbourne, Parkville, VIC, Australia
| | - David A Simpson
- School of Physics, University of Melbourne, Parkville, VIC, Australia
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11
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Yu B, Cheng C, Wu Y, Guo L, Kong D, Zhang Z, Wang Y, Zheng E, Liu Y, He Y. Interactions of ferritin with scavenger receptor class A members. J Biol Chem 2020; 295:15727-15741. [PMID: 32907880 DOI: 10.1074/jbc.ra120.014690] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/31/2020] [Indexed: 12/16/2022] Open
Abstract
Scavenger receptors are a superfamily of membrane-bound receptors that recognize both self and nonself targets. Scavenger receptor class A (SR-A) has five known members (SCARA1 to -5 or SR-A1 to -A5), which are type II transmembrane proteins that form homotrimers on the cell surface. SR-A members recognize various ligands and are involved in multiple biological pathways. Among them, SCARA5 can function as a ferritin receptor; however, the interaction between SCARA5 and ferritin has not been fully characterized. Here, we determine the crystal structures of the C-terminal scavenger receptor cysteine-rich (SRCR) domain of both human and mouse SCARA5 at 1.7 and 2.5 Å resolution, respectively, revealing three Ca2+-binding sites on the surface. Using biochemical assays, we show that the SRCR domain of SCARA5 recognizes ferritin in a Ca2+-dependent manner, and both L- and H-ferritin can be recognized by SCARA5 through the SRCR domain. Furthermore, the potential binding region of SCARA5 on the surface of ferritin is explored by mutagenesis studies. We also examine the interactions of ferritin with other SR-A members and find that SCARA1 (SR-A1, CD204) and MARCO (SR-A2, SCARA2), which are highly expressed on macrophages, also interact with ferritin. By contrast, SCARA3 and SCARA4, the two SR-A members without the SRCR domain, have no detectable binding with ferritin. Overall, these results provide a mechanistic view regarding the interactions between the SR-A members and ferritin that may help to understand the regulation of ferritin homeostasis by scavenger receptors.
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Affiliation(s)
- Bowen Yu
- Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Chen Cheng
- Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Yichun Wu
- Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Luqiang Guo
- Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Dandan Kong
- Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Ze Zhang
- Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Yuanyuan Wang
- Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Enlin Zheng
- Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Yingbin Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongning He
- Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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12
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Xiao G, Liu ZH, Zhao M, Wang HL, Zhou B. Transferrin 1 Functions in Iron Trafficking and Genetically Interacts with Ferritin in Drosophila melanogaster. Cell Rep 2020; 26:748-758.e5. [PMID: 30650364 DOI: 10.1016/j.celrep.2018.12.053] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 10/31/2018] [Accepted: 12/11/2018] [Indexed: 12/23/2022] Open
Abstract
Iron metabolism is an essential process that when dysregulated causes disease. Mammalian serum transferrin (TF) plays a primary role in delivering iron to cells. To improve our understanding of the conservation of iron metabolism between species, we investigate here the function of the TF homolog in Drosophila melanogaster, transferrin 1 (Tsf1). Tsf1 knockdown results in iron accumulation in the gut and iron deficiency in the fat body (which is analogous to the mammalian liver). Fat body-derived Tsf1 localizes to the gut surface, suggesting that Tsf1 functions in trafficking iron between the gut and the fat body, similar to TF in mammals. Moreover, Tsf1 knockdown strongly suppresses the phenotypic effects of ferritin (Fer1HCH) RNAi, an established iron trafficker in Drosophila. We propose that Tsf1 and ferritin compete for iron in the Drosophila intestine and demonstrate the value of using Drosophila for investigating iron trafficking and the evolution of systemic iron regulation.
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Affiliation(s)
- Guiran Xiao
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, China.
| | - Zhi-Hua Liu
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, China
| | - Mengran Zhao
- State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Hui-Li Wang
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, China.
| | - Bing Zhou
- State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
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13
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Dziuba N, Hardy J, Lindahl PA. Low-molecular-mass iron complexes in blood plasma of iron-deficient pigs do not originate directly from nutrient iron. Metallomics 2019; 11:1900-1911. [PMID: 31603444 PMCID: PMC6854301 DOI: 10.1039/c9mt00152b] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Nutrient iron entering the blood binds transferrin (TFN)d, which delivers iron to cells in the body. In healthy individuals, ∼30% of TFN is iron-bound while the remainder is unbound (apo-TFN). TFN saturates the plasma of individuals with iron-overload diseases such as hereditary hemochromatosis, prompting release of a poorly-defined low-molecular-mass (LMM) iron species called non-transferrin-bound iron (NTBI). An experiment was devised to directly detect NTBI in plasma of iron-deficient pigs and to assess the role of the liver which is known to bind NTBI. Catheters were surgically installed in the portal vein (PV) and either the caudal vena cava or the cranial vena cava. After the animals recovered, 57Fe II ascorbate was injected into the stomach via a feeding tube. Blood was removed through the catheters before and after injection; plasma became 57Fe-enriched after injection. 57Fe-enriched plasma was passed through a 10 kDa cutoff membrane and the flow-through solution (FTS) was subjected to size-exclusion liquid chromatography (LC). The eluent flowed into an ICP-MS where 56Fe and 57Fe were detected. Low-intensity iron peaks with masses of 400-1600 Da were observed, but none became enriched in 57Fe after injection. Rather, the injected 57Fe bound to apo-TFN. Viewed naively, this implies that nutrient-derived 57Fe in healthy mammals passes from the intestines to apo-TFN without first entering the blood as a LMM intermediate. In this case, nutrient iron exported from intestinal enterocytes of healthy individuals may quickly bind apo-TFN such that LMM iron species do not accumulate in blood plasma. Some 57Fe from the FTS may have adsorbed onto the column. In any event, the LMM iron species in plasma that eluted from the column must have originated from iron stored within the body, perhaps in macrophages - not directly from nutrient iron absorption. The liver absorbed and released LMM iron species, but the effect was modest, consistent with its role as a dynamic iron buffer. Passage through the liver also altered the distribution of different forms of TFN present in the PV.
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Affiliation(s)
- Nathaniel Dziuba
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA
| | - Joanne Hardy
- Department of Veterinary Surgery, Veterinary Medicine and Biosciences, College Station, TX 77843-4475, USA
| | - Paul A Lindahl
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA and Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA.
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14
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Iron-Induced Liver Injury: A Critical Reappraisal. Int J Mol Sci 2019; 20:ijms20092132. [PMID: 31052166 PMCID: PMC6539962 DOI: 10.3390/ijms20092132] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 04/25/2019] [Accepted: 04/27/2019] [Indexed: 12/12/2022] Open
Abstract
Iron is implicated in the pathogenesis of a number of human liver diseases. Hereditary hemochromatosis is the classical example of a liver disease caused by iron, but iron is commonly believed to contribute to the progression of other forms of chronic liver disease such as hepatitis C infection and nonalcoholic fatty liver disease. In this review, we present data from cell culture experiments, animal models, and clinical studies that address the hepatotoxicity of iron. These data demonstrate that iron overload is only weakly fibrogenic in animal models and rarely causes serious liver damage in humans, calling into question the concept that iron overload is an important cause of hepatotoxicity. In situations where iron is pathogenic, iron-induced liver damage may be potentiated by coexisting inflammation, with the resulting hepatocyte necrosis an important factor driving the fibrogenic response. Based on the foregoing evidence that iron is less hepatotoxic than is generally assumed, claims that assign a causal role to iron in liver injury in either animal models or human liver disease should be carefully evaluated.
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15
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Leaf DE, Rajapurkar M, Lele SS, Mukhopadhyay B, Boerger EAS, Mc Causland FR, Eisenga MF, Singh K, Babitt JL, Kellum JA, Palevsky PM, Christov M, Waikar SS. Iron, Hepcidin, and Death in Human AKI. J Am Soc Nephrol 2019; 30:493-504. [PMID: 30737269 PMCID: PMC6405140 DOI: 10.1681/asn.2018100979] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 12/30/2018] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Iron is a key mediator of AKI in animal models, but data on circulating iron parameters in human AKI are limited. METHODS We examined results from the ARF Trial Network study to assess the association of plasma catalytic iron, total iron, transferrin, ferritin, free hemoglobin, and hepcidin with 60-day mortality. Participants included critically ill patients with AKI requiring RRT who were enrolled in the study. RESULTS Of the 807 study participants, 409 (51%) died by day 60. In both unadjusted and multivariable adjusted models, higher plasma concentrations of catalytic iron were associated with a significantly greater risk of death, as were lower concentrations of hepcidin. After adjusting for other factors, patients with catalytic iron levels in the highest quintile versus the lowest quintile had a 4.06-fold increased risk of death, and patients with hepcidin levels in the lowest quintile versus the highest quintile of hepcidin had a 3.87-fold increased risk of death. These findings were consistent across multiple subgroups. Other iron markers were also associated with death, but the magnitude of the association was greatest for catalytic iron and hepcidin. Higher plasma concentrations of catalytic iron and lower concentrations of hepcidin are each independently associated with mortality in critically ill patients with AKI requiring RRT. CONCLUSIONS These findings suggest that plasma concentrations of catalytic iron and hepcidin may be useful prognostic markers in patients with AKI. Studies are needed to determine whether strategies to reduce catalytic iron or increase hepcidin might be beneficial in this patient population.
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Affiliation(s)
- David E Leaf
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
| | | | | | | | - Emily A S Boerger
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | | | - Michele F Eisenga
- Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Departments of
| | - Karandeep Singh
- Learning Health Sciences and
- Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Jodie L Babitt
- Nephrology Division, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts
| | - John A Kellum
- Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Paul M Palevsky
- Renal Section, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
- Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and
| | - Marta Christov
- Department of Medicine, New York Medical College, Valhalla, New York
| | - Sushrut S Waikar
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts
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16
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Cadenas B, Fita-Torró J, Bermúdez-Cortés M, Hernandez-Rodriguez I, Fuster JL, Llinares ME, Galera AM, Romero JL, Pérez-Montero S, Tornador C, Sanchez M. L-Ferritin: One Gene, Five Diseases; from Hereditary Hyperferritinemia to Hypoferritinemia-Report of New Cases. Pharmaceuticals (Basel) 2019; 12:ph12010017. [PMID: 30678075 PMCID: PMC6469184 DOI: 10.3390/ph12010017] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Revised: 01/18/2019] [Accepted: 01/19/2019] [Indexed: 01/13/2023] Open
Abstract
Ferritin is a multimeric protein composed of light (L-ferritin) and heavy (H-ferritin) subunits that binds and stores iron inside the cell. A variety of mutations have been reported in the L-ferritin subunit gene (FTL gene) that cause the following five diseases: (1) hereditary hyperferritinemia with cataract syndrome (HHCS), (2) neuroferritinopathy, a subtype of neurodegeneration with brain iron accumulation (NBIA), (3) benign hyperferritinemia, (4) L-ferritin deficiency with autosomal dominant inheritance, and (5) L-ferritin deficiency with autosomal recessive inheritance. Defects in the FTL gene lead to abnormally high levels of serum ferritin (hyperferritinemia) in HHCS and benign hyperferritinemia, while low levels (hypoferritinemia) are present in neuroferritinopathy and in autosomal dominant and recessive L-ferritin deficiency. Iron disturbances as well as neuromuscular and cognitive deficits are present in some, but not all, of these diseases. Here, we identified two novel FTL variants that cause dominant L-ferritin deficiency and HHCS (c.375+2T > A and 36_42delCAACAGT, respectively), and one previously reported variant (Met1Val) that causes dominant L-ferritin deficiency. Globally, genetic changes in the FTL gene are responsible for multiple phenotypes and an accurate diagnosis is useful for appropriate treatment. To help in this goal, we included a diagnostic algorithm for the detection of diseases caused by defects in FTL gene.
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Affiliation(s)
- Beatriz Cadenas
- Whole Genix SL., 08021 Barcelona, Spain.
- Iron Metabolism: Regulation and Diseases Group, Josep Carreras Leukemia Research Institute (IJC), Campus Can Ruti, Badalona, 08916 Barcelona, Spain.
- Experimental Sciences and Technology Department, Universitat de Vic-Universitat Central de Catalunya, 08500 Vic, Spain.
| | - Josep Fita-Torró
- BloodGenetics SL, Esplugues de Llobregat, 08950 Barcelona, Spain.
| | - Mar Bermúdez-Cortés
- Pediatric OncoHematology Service, Clinic University Hospital Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain.
| | - Inés Hernandez-Rodriguez
- Hematology Service, University Hospital Germans Trias i Pujol (HGTiP), Institut Català d'Oncologia (ICO), Badalona, 08916 Barcelona, Spain.
| | - José Luis Fuster
- Pediatric OncoHematology Service, Clinic University Hospital Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain.
| | - María Esther Llinares
- Pediatric OncoHematology Service, Clinic University Hospital Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain.
| | - Ana María Galera
- Pediatric OncoHematology Service, Clinic University Hospital Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain.
| | - Julia Lee Romero
- Biomedical Engineering Department, University of Texas at Austin, Austin, TX 78712, USA.
| | | | - Cristian Tornador
- Whole Genix SL., 08021 Barcelona, Spain.
- BloodGenetics SL, Esplugues de Llobregat, 08950 Barcelona, Spain.
| | - Mayka Sanchez
- BloodGenetics SL, Esplugues de Llobregat, 08950 Barcelona, Spain.
- Program of Predictive and Personalised Medicine of Cancer (PMPPC), Institut d'Investigació Germans Trias i Pujol (IGTP), Campus Can Ruti, Badalona, 08916 Barcelona, Spain.
- Iron Metabolism: Regulation and Diseases Group, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC), 08195 Barcelona, Spain.
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17
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du Plooy JN, Bester J, Pretorius E. Eryptosis in Haemochromatosis: Implications for rheology. Clin Hemorheol Microcirc 2018; 69:457-469. [PMID: 29710680 DOI: 10.3233/ch-170325] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Haemochromatosis is an iron-storage disease with different genetic mutations, characterized by an increased intestinal absorption of iron, resulting in a deposition of excessive amounts of iron in parenchymal cells. When the iron is released in the blood, it is left in an unliganded form, where it can participate in Haber-Weiss and Fenton reactions, creating hydroxyl radicals. Erythrocytes (RBCs) are particularly vulnerable to hydroxyl radical damage, which can result in eryptosis (programmed cell death similar to apoptosis). STUDY DESIGN AND METHODS Here, we used flow cytometry to study the presence of eryptosis in the main genotypic variations of HFE (heterozygous and homozygous C282Y; H63D; C282Y/H63D). We also viewed RBCs from the different mutations using super-resolution Airyscan confocal microscopy. RESULTS Flow cytometry showed significant changes in membrane biochemistry, indicated by the presence of phosphatidylserine (PS) proteins on the outer leaflet of the membrane, as well as increased intracellular calpain. This was found in all of the studied mutations. Airyscan fluorescence revealed PS flip and also microparticles from RBCs. Such microparticles are known to be pro-inflammatory. CONCLUSION We conclude that RBC pathology is present in all the studied HFE mutations, even in low penetrance mutations, and this might affect rheology in these individuals.
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Affiliation(s)
| | - Janette Bester
- Department of Physiology, University of Pretoria, South Africa
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18
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Kell DB, Pretorius E. No effects without causes: the Iron Dysregulation and Dormant Microbes hypothesis for chronic, inflammatory diseases. Biol Rev Camb Philos Soc 2018; 93:1518-1557. [PMID: 29575574 PMCID: PMC6055827 DOI: 10.1111/brv.12407] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 02/12/2018] [Accepted: 02/15/2018] [Indexed: 12/11/2022]
Abstract
Since the successful conquest of many acute, communicable (infectious) diseases through the use of vaccines and antibiotics, the currently most prevalent diseases are chronic and progressive in nature, and are all accompanied by inflammation. These diseases include neurodegenerative (e.g. Alzheimer's, Parkinson's), vascular (e.g. atherosclerosis, pre-eclampsia, type 2 diabetes) and autoimmune (e.g. rheumatoid arthritis and multiple sclerosis) diseases that may appear to have little in common. In fact they all share significant features, in particular chronic inflammation and its attendant inflammatory cytokines. Such effects do not happen without underlying and initially 'external' causes, and it is of interest to seek these causes. Taking a systems approach, we argue that these causes include (i) stress-induced iron dysregulation, and (ii) its ability to awaken dormant, non-replicating microbes with which the host has become infected. Other external causes may be dietary. Such microbes are capable of shedding small, but functionally significant amounts of highly inflammagenic molecules such as lipopolysaccharide and lipoteichoic acid. Sequelae include significant coagulopathies, not least the recently discovered amyloidogenic clotting of blood, leading to cell death and the release of further inflammagens. The extensive evidence discussed here implies, as was found with ulcers, that almost all chronic, infectious diseases do in fact harbour a microbial component. What differs is simply the microbes and the anatomical location from and at which they exert damage. This analysis offers novel avenues for diagnosis and treatment.
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Affiliation(s)
- Douglas B. Kell
- School of ChemistryThe University of Manchester, 131 Princess StreetManchesterLancsM1 7DNU.K.
- The Manchester Institute of BiotechnologyThe University of Manchester, 131 Princess StreetManchesterLancsM1 7DNU.K.
- Department of Physiological SciencesStellenbosch University, Stellenbosch Private Bag X1Matieland7602South Africa
| | - Etheresia Pretorius
- Department of Physiological SciencesStellenbosch University, Stellenbosch Private Bag X1Matieland7602South Africa
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19
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Macdougall IC, Bircher AJ, Eckardt KU, Obrador GT, Pollock CA, Stenvinkel P, Swinkels DW, Wanner C, Weiss G, Chertow GM, Adamson JW, Akizawa T, Anker SD, Auerbach M, Bárány P, Besarab A, Bhandari S, Cabantchik I, Collins AJ, Coyne DW, de Francisco ÁL, Fishbane S, Gaillard CA, Ganz T, Goldsmith DJ, Hershko C, Jankowska EA, Johansen KL, Kalantar-Zadeh K, Kalra PA, Kasiske BL, Locatelli F, Małyszko J, Mayer G, McMahon LP, Mikhail A, Nemeth E, Pai AB, Parfrey PS, Pecoits-Filho R, Roger SD, Rostoker G, Rottembourg J, Singh AK, Slotki I, Spinowitz BS, Tarng DC, Tentori F, Toblli JE, Tsukamoto Y, Vaziri ND, Winkelmayer WC, Wheeler DC, Zakharova E. Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int 2016; 89:28-39. [DOI: 10.1016/j.kint.2015.10.002] [Citation(s) in RCA: 194] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 09/22/2015] [Accepted: 09/29/2015] [Indexed: 12/21/2022]
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20
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Bresgen N, Eckl PM. Oxidative stress and the homeodynamics of iron metabolism. Biomolecules 2015; 5:808-47. [PMID: 25970586 PMCID: PMC4496698 DOI: 10.3390/biom5020808] [Citation(s) in RCA: 165] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Revised: 04/21/2015] [Accepted: 04/22/2015] [Indexed: 12/12/2022] Open
Abstract
Iron and oxygen share a delicate partnership since both are indispensable for survival, but if the partnership becomes inadequate, this may rapidly terminate life. Virtually all cell components are directly or indirectly affected by cellular iron metabolism, which represents a complex, redox-based machinery that is controlled by, and essential to, metabolic requirements. Under conditions of increased oxidative stress—i.e., enhanced formation of reactive oxygen species (ROS)—however, this machinery may turn into a potential threat, the continued requirement for iron promoting adverse reactions such as the iron/H2O2-based formation of hydroxyl radicals, which exacerbate the initial pro-oxidant condition. This review will discuss the multifaceted homeodynamics of cellular iron management under normal conditions as well as in the context of oxidative stress.
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Affiliation(s)
- Nikolaus Bresgen
- Department of Cell Biology, University of Salzburg, Hellbrunnerstrasse 34, 5020 Salzburg, Austria.
| | - Peter M Eckl
- Department of Cell Biology, University of Salzburg, Hellbrunnerstrasse 34, 5020 Salzburg, Austria.
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21
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Ren Y, Walczyk T. Quantification of ferritin bound iron in human serum using species-specific isotope dilution mass spectrometry. Metallomics 2015; 6:1709-17. [PMID: 25008269 DOI: 10.1039/c4mt00127c] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Ferritin is a hollow sphere protein composed of 24 subunits that can store up to 4500 iron atoms in its inner cavity. It is mainly found in the liver and spleen but also in serum at trace levels. Serum ferritin is considered as the best single indicator in assessing body iron stores except liver or bone marrow biopsy. However, it is confounded by other disease conditions. Ferritin bound iron (FBI) and ferritin saturation have been suggested as more robust biomarkers. The current techniques for FBI determination are limited by low antibody specificity, low instrument sensitivity and possible analyte losses during sample preparation. The need for a highly sensitive and reliable method is widely recognized. Here we describe a novel technique to detect serum FBI using species-specific isotope dilution mass spectrometry (SS-IDMS). [(57)Fe]-ferritin was produced by biosynthesis and in vitro labeling with the (57)Fe spike in the form of [(57)Fe]-citrate after cell lysis and heat treatment. [(57)Fe]-ferritin for sample spiking was further purified by fast liquid protein chromatography. Serum ferritin and added [(57)Fe]-ferritin were separated from other iron species by ultrafiltration followed by isotopic analysis of FBI using negative thermal ionization mass spectrometry. Repeatability of our assay is 8% with an absolute detection limit of 18 ng FBI in the sample. As compared to other speciation techniques, SS-IDMS offers maximum control over sample losses and species conversion during analysis. The described technique may therefore serve as a reference technique for clinical applications of FBI as a new biomarker for assessing body iron status.
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Affiliation(s)
- Yao Ren
- Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore117543.
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22
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Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics 2014; 6:748-73. [PMID: 24549403 DOI: 10.1039/c3mt00347g] [Citation(s) in RCA: 414] [Impact Index Per Article: 37.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
"Serum ferritin" presents a paradox, as the iron storage protein ferritin is not synthesised in serum yet is to be found there. Serum ferritin is also a well known inflammatory marker, but it is unclear whether serum ferritin reflects or causes inflammation, or whether it is involved in an inflammatory cycle. We argue here that serum ferritin arises from damaged cells, and is thus a marker of cellular damage. The protein in serum ferritin is considered benign, but it has lost (i.e. dumped) most of its normal complement of iron which when unliganded is highly toxic. The facts that serum ferritin levels can correlate with both disease and with body iron stores are thus expected on simple chemical kinetic grounds. Serum ferritin levels also correlate with other phenotypic readouts such as erythrocyte morphology. Overall, this systems approach serves to explain a number of apparent paradoxes of serum ferritin, including (i) why it correlates with biomarkers of cell damage, (ii) why it correlates with biomarkers of hydroxyl radical formation (and oxidative stress) and (iii) therefore why it correlates with the presence and/or severity of numerous diseases. This leads to suggestions for how one might exploit the corollaries of the recognition that serum ferritin levels mainly represent a consequence of cell stress and damage.
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Affiliation(s)
- Douglas B Kell
- School of Chemistry and The Manchester Institute of Biotechnology, The University of Manchester, 131, Princess St, Manchester M1 7DN, Lancs, UK.
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23
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Abstract
Iron is essential for the normal physiological function of all organisms. In humans it is required for a plethora of biochemical roles including the transport of oxygen in the blood and energy production in the mitochondria. However, iron is also highly cytotoxic when present at high levels as it readily participates in oxidation-reduction reactions that lead to the generation of reactive oxygen species. One unique feature of iron biology is the lack of excretory mechanisms to remove excess iron from the body. Therefore, the concerted action of several genes and proteins working together to regulate the movement of iron across cell membranes, its storage in peripheral tissues and its physiological utilization in the body is essential for maintaining iron homeostasis. Humans are exposed to iron in a number of chemical forms (haem or non-haem; ferric or ferrous). This chapter will describe how humans acquire iron from their diet; the subsequent delivery of iron to its sites of utilization and storage; and how iron is recycled from effete erythrocytes for re-use in metabolism. Mutations in a number of the genes controlling iron metabolism have been identified and study of the pathological consequences of these mutations has allowed us to gain a greater understanding of how the body senses changes in iron status and coordinates its transport, storage and utilization to maintain homeostasis.
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Affiliation(s)
- Paul Sharp
- Diabetes & Nutritional Sciences Division, King's College London, School of Medicine Franklin Wilkins Building, 150 Stamford Street London SE1 9NH UK
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24
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Alkhateeb AA, Connor JR. The significance of ferritin in cancer: anti-oxidation, inflammation and tumorigenesis. Biochim Biophys Acta Rev Cancer 2013; 1836:245-54. [PMID: 23891969 DOI: 10.1016/j.bbcan.2013.07.002] [Citation(s) in RCA: 125] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 07/09/2013] [Accepted: 07/18/2013] [Indexed: 12/16/2022]
Abstract
The iron storage protein ferritin has been continuously studied for over 70years and its function as the primary iron storage protein in cells is well established. Although the intracellular functions of ferritin are for the most part well-characterized, the significance of serum (extracellular) ferritin in human biology is poorly understood. Recently, several lines of evidence have demonstrated that ferritin is a multi-functional protein with possible roles in proliferation, angiogenesis, immunosuppression, and iron delivery. In the context of cancer, ferritin is detected at higher levels in the sera of many cancer patients, and the higher levels correlate with aggressive disease and poor clinical outcome. Furthermore, ferritin is highly expressed in tumor-associated macrophages which have been recently recognized as having critical roles in tumor progression and therapy resistance. These characteristics suggest ferritin could be an attractive target for cancer therapy because its down-regulation could disrupt the supportive tumor microenvironment, kill cancer cells, and increase sensitivity to chemotherapy. In this review, we provide an overview of the current knowledge on the function and regulation of ferritin. Moreover, we examine the literature on ferritin's contributions to tumor progression and therapy resistance, in addition to its therapeutic potential.
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Affiliation(s)
- Ahmed A Alkhateeb
- Department of Neurosurgery, The Pennsylvania State University Hershey Medical Center, Hershey, PA, USA
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25
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Ferritin stimulates breast cancer cells through an iron-independent mechanism and is localized within tumor-associated macrophages. Breast Cancer Res Treat 2013; 137:733-44. [PMID: 23306463 DOI: 10.1007/s10549-012-2405-x] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Accepted: 12/29/2012] [Indexed: 10/27/2022]
Abstract
Tumor-associated macrophages play a critical role in breast tumor progression; however, it is still unclear what effector molecular mechanisms they employ to impact tumorigenesis. Ferritin is the primary intracellular iron storage protein and is also abundant in circulation. In breast cancer patients, ferritin is detected at higher levels in both serum and tumor lysates, and its increase correlates with poor clinical outcome. In this study, we comprehensively examined the distribution of ferritin in normal and malignant breast tissue at different stages in tumor development. Decreased ferritin expression in cancer cells but increased infiltration of ferritin-rich CD68-positive macrophages was observed with increased tumor histological grade. Interestingly, ferritin stained within the stroma surrounding tumors suggesting local release within the breast. In cell culture, macrophages, but not breast cancer cells, were capable of ferritin secretion, and this secretion was further increased in response to pro-inflammatory cytokines. We next examined the possible functional significance of extracellular ferritin in a breast cancer cell culture model. Ferritin stimulated the proliferation of the epithelial breast cancer cell lines MCF7 and T47D. Moreover, this proliferative effect was independent of the iron content of ferritin and did not increase intracellular iron levels in cancer cells indicating a novel iron-independent function for this protein. Together, these findings suggest that the release of ferritin by infiltrating macrophages in breast tumors may represent an inflammatory effector mechanism by which ferritin directly stimulates tumorigenesis.
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26
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Tang X, Zhou B. Ferritin is the key to dietary iron absorption and tissue iron detoxification in Drosophila melanogaster. FASEB J 2012; 27:288-98. [PMID: 23064556 DOI: 10.1096/fj.12-213595] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Mammalian ferritin is predominantly in the cytosol, with a minor portion found in plasma. In most insects, including Drosophila melanogaster, ferritin belongs to the secretory type. The functional role of secretory ferritin in iron homeostasis remains poorly understood in insects as well as in mammalians. Here we used Drosophila to dissect the involvement of ferritin in insect iron metabolism. Midgut-specific knockdown of ferritin resulted in iron accumulation in the gut but systemic iron deficiency (37% control), accompanied by retarded development and reduced survival (3% survival), and was rescued by dietary iron supplementation (50% survival) or exacerbated by iron depletion (0% survival). These results suggest an essential role of ferritin in removing iron from enterocytes across the basolateral membrane. Expression of wild-type ferritin in the midgut, especially in the iron cell region, could significantly rescue ferritin-null mutants (first-instar larvae rescued up to early adults), indicating iron deficiency as the major cause of early death for ferritin flies. In many nonintestinal tissues, tissue-specific ferritin knockdown also caused local iron accumulation (100% increase) and resulted in severe tissue damage, as evidenced by cell loss. Overall, our study demonstrated Drosophila ferritin is essential to two key aspects of iron homeostasis: dietary iron absorption and tissue iron detoxification.
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Affiliation(s)
- Xiaona Tang
- State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing, China
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27
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Synthetic and natural iron chelators: therapeutic potential and clinical use. Future Med Chem 2011; 1:1643-70. [PMID: 21425984 DOI: 10.4155/fmc.09.121] [Citation(s) in RCA: 173] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Iron-chelation therapy has its origins in the treatment of iron-overload syndromes. For many years, the standard for this purpose has been deferoxamine. Recently, considerable progress has been made in identifying synthetic chelators with improved pharmacologic properties relative to deferoxamine. Most notable are deferasirox (Exjade(®)) and deferiprone (Ferriprox(®)), which are now available clinically. In addition to treatment of iron overload, there is an emerging role for iron chelators in the treatment of diseases characterized by oxidative stress, including cardiovascular disease, atherosclerosis, neurodegenerative diseases and cancer. While iron is not regarded as the underlying cause of these diseases, it does play an important role in disease progression, either through promotion of cellular growth and proliferation or through participation in redox reactions that catalyze the formation of reactive oxygen species and increase oxidative stress. Thus, iron chelators may be of therapeutic benefit in many of these conditions. Phytochemicals, many of which bind iron, may also owe some of their beneficial properties to iron chelation. This review will focus on the advances in iron-chelation therapy for the treatment of iron-overload disease and cancer, as well as neurodegenerative and chronic inflammatory diseases. Established and novel iron chelators will be discussed, as well as the emerging role of dietary plant polyphenols that effectively modulate iron biochemistry.
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A possible role for secreted ferritin in tissue iron distribution. J Neural Transm (Vienna) 2011; 118:337-47. [PMID: 21298454 DOI: 10.1007/s00702-011-0582-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2010] [Accepted: 01/09/2011] [Indexed: 01/19/2023]
Abstract
Ferritin is known as a well-conserved iron detoxification and storage protein that is found in the cytosol of many prokaryotic and eukaryotic organisms. In insects and worms, ferritin has evolved into a classically secreted protein that transports iron systemically. Mammalian ferritins are found intracellularly in the cytosol, as well as in the nucleus, the endo-lysosomal compartment and the mitochondria. Extracellular ferritin is found in fluids such as serum and synovial and cerebrospinal fluids. We recently characterized the biophysical properties, secretion mechanism and cellular origin of mouse serum ferritin, which is actively secreted by a non-classical pathway involving lysosomal processing. Here, we review the data to support a hypothesis that intracellular and extracellular ferritin may play a role in intra- and intercellular redistribution of iron.
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The many faces of the octahedral ferritin protein. Biometals 2011; 24:489-500. [PMID: 21267633 DOI: 10.1007/s10534-011-9415-8] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2010] [Accepted: 01/13/2011] [Indexed: 12/14/2022]
Abstract
Iron is an essential trace nutrient required for the active sites of many enzymes, electron transfer and oxygen transport proteins. In contrast, to its important biological roles, iron is a catalyst for reactive oxygen species (ROS). Organisms must acquire iron but must protect against oxidative damage. Biology has evolved siderophores, hormones, membrane transporters, and iron transport and storage proteins to acquire sufficient iron but maintain iron levels at safe concentrations that prevent iron from catalyzing the formation of ROS. Ferritin is an important hub for iron metabolism because it sequesters iron during times of iron excess and releases iron during iron paucity. Ferritin is expressed in response to oxidative stress and is secreted into the extracellular matrix and into the serum. The iron sequestering ability of ferritin is believed to be the source of the anti-oxidant properties of ferritin. In fact, ferritin has been used as a biomarker for disease because it is synthesized in response to oxidative damage and inflammation. The function of serum ferritin is poorly understood, however serum ferritin concentrations seem to correlate with total iron stores. Under certain conditions, ferritin is also associated with pro-oxidant activity. The source of this switch from anti-oxidant to pro-oxidant has not been established but may be associated with unregulated iron release from ferritin. Recent reports demonstrate that ferritin is involved in other aspects of biology such as cell activation, development, immunity and angiogenesis. This review examines ferritin expression and secretion in correlation with anti-oxidant activity and with respect to these new functions. In addition, conditions that lead to pro-oxidant conditions are considered.
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Wang W, Knovich MA, Coffman LG, Torti FM, Torti SV. Serum ferritin: Past, present and future. BIOCHIMICA ET BIOPHYSICA ACTA 2010; 1800:760-9. [PMID: 20304033 PMCID: PMC2893236 DOI: 10.1016/j.bbagen.2010.03.011] [Citation(s) in RCA: 557] [Impact Index Per Article: 37.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/09/2009] [Revised: 03/11/2010] [Accepted: 03/13/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND Serum ferritin was discovered in the 1930s, and was developed as a clinical test in the 1970s. Many diseases are associated with iron overload or iron deficiency. Serum ferritin is widely used in diagnosing and monitoring these diseases. SCOPE OF REVIEW In this chapter, we discuss the role of serum ferritin in physiological and pathological processes and its use as a clinical tool. MAJOR CONCLUSIONS Although many aspects of the fundamental biology of serum ferritin remain surprisingly unclear, a growing number of roles have been attributed to extracellular ferritin, including newly described roles in iron delivery, angiogenesis, inflammation, immunity, signaling and cancer. GENERAL SIGNIFICANCE Serum ferritin remains a clinically useful tool. Further studies on the biology of this protein may provide new biological insights.
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Affiliation(s)
- Wei Wang
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
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31
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Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood 2010; 116:1574-84. [PMID: 20472835 DOI: 10.1182/blood-2009-11-253815] [Citation(s) in RCA: 327] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The serum ferritin concentration is a clinical parameter measured widely for the differential diagnosis of anemia. Its levels increase with elevations of tissue iron stores and with inflammation, but studies on cellular sources of serum ferritin as well as its subunit composition, degree of iron loading and glycosylation have given rise to conflicting results. To gain further understanding of serum ferritin, we have used traditional and modern methodologies to characterize mouse serum ferritin. We find that both splenic macrophages and proximal tubule cells of the kidney are possible cellular sources for serum ferritin and that serum ferritin is secreted by cells rather than being the product of a cytosolic leak from damaged cells. Mouse serum ferritin is composed mostly of L-subunits, whereas it contains few H-subunits and iron content is low. L-subunits of serum ferritin are frequently truncated at the C-terminus, giving rise to a characteristic 17-kD band that has been previously observed in lysosomal ferritin. Taken together with the fact that mouse serum ferritin is not detectably glycosylated, we propose that mouse serum ferritin is secreted through the nonclassical lysosomal secretory pathway.
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Spada PL, Rossi C, Alimonti A, Bocca B, Ricerca BM, Bocci MG, Carvelli M, Vulpio C, Luciani G, De Sole P. Iron, zinc and aluminium ferritin content of hemodialysis hyperferritinemic patients: comparison with other hyperferritinemic clinical conditions and normoferritinemic blood donors. Clin Biochem 2009; 42:1654-7. [PMID: 19651118 DOI: 10.1016/j.clinbiochem.2009.07.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2009] [Revised: 06/19/2009] [Accepted: 07/19/2009] [Indexed: 11/28/2022]
Abstract
The present study describes the specific content of ferritin iron, zinc and aluminium in four different groups: 1) hemodialysis hyperferritinemic patients; 2) septic patients; 3) iron overloaded patients with hematologic diseases; and 4) blood donors. In all four groups high levels of aluminium and zinc were found in addition to those of iron. However, the sum of the ferritin ions of the control group is significantly higher than that of the other three groups. Furthermore, while ferritin of hemodialysis patients has the same molecular ratio of metal ions as control group (high Al content vs. Fe and Zn), a lower Al/Fe ratio is found both in septic and hematological patients. The results of the present paper might help to explain the high percentage of hyperferritinemia found in hemodialysis patients also in presence of low transferrin saturation and in absence of inflammatory markers. Moreover, the high content of ions other than iron in the ferritin core leads us to believe that ferritin is not only an iron storage protein but rather a regulator of redox active ions.
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Affiliation(s)
- P L Spada
- Department of Surgery, Catholic University of Sacred Heart, Largo A. Gemelli 8, Rome, Italy
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Arosio P, Ingrassia R, Cavadini P. Ferritins: a family of molecules for iron storage, antioxidation and more. BIOCHIMICA ET BIOPHYSICA ACTA 2009; 1790:589-99. [PMID: 18929623 DOI: 10.1016/j.bbagen.2008.09.004] [Citation(s) in RCA: 640] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2008] [Revised: 08/28/2008] [Accepted: 09/09/2008] [Indexed: 01/19/2023]
Abstract
Ferritins are characterized by highly conserved three-dimensional structures similar to spherical shells, designed to accommodate large amounts of iron in a safe, soluble and bioavailable form. They can have different architectures with 12 or 24 equivalent or non-equivalent subunits, all surrounding a large cavity. All ferritins readily interact with Fe(II) to induce its oxidation and deposition in the cavity in a mineral form, in a reaction that is catalyzed by a ferroxidase center. This is an anti-oxidant activity that consumes Fe(II) and peroxides, the reagents that produce toxic free radicals in the Fenton reaction. The mechanism of ferritin iron incorporation has been characterized in detail, while that of iron release and recycling has been less thoroughly studied. Generally ferritin expression is regulated by iron and by oxidative damage, and in vertebrates it has a central role in the control of cellular iron homeostasis. Ferritin is mostly cytosolic but is found also in mammalian mitochondria and nuclei, in plant plastids and is secreted in insects. In vertebrates the cytosolic ferritins are composed of H and L subunit types and their assembly in a tissues specific ratio that permits flexibility to adapt to cell needs. The H-ferritin can translocate to the nuclei in some cell types to protect DNA from iron toxicity, or can be actively secreted, accomplishing various functions. The mitochondrial ferritin is found in mammals, it has a restricted tissue distribution and it seems to protect the mitochondria from iron toxicity and oxidative damage. The various functions attributed to the cytosolic, nuclear, secretory and mitochondrial ferritins are discussed.
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Affiliation(s)
- Paolo Arosio
- Dipartimento Materno Infantile e Tecnologie Biomediche, Università di Brescia, and A.O. Spedali Civili, Brescia, Italy.
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Santambrogio P, Cozzi A, Levi S, Arosio P. Human serum ferritin G-peptide is recognized by anti-L ferritin subunit antibodies and concanavalin-A. Br J Haematol 2008. [DOI: 10.1111/j.1365-2141.1987.00231.x-i1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Abstract
The liver plays a central role in iron metabolism. It is the major storage site for iron and also expresses a complex range of molecules which are involved in iron transport and regulation of iron homeostasis. An increasing number of genes associated with hepatic iron transport or regulation have been identified. These include transferrin receptors (TFR1 and 2), a ferrireductase (STEAP3), the transporters divalent metal transporter-1 (DMT1) and ferroportin (FPN) as well as the haemochromatosis protein, HFE and haemojuvelin (HJV), which are signalling molecules. Many of these genes also participate in iron regulatory pathways which focus on the hepatic peptide hepcidin. However, we are still only beginning to understand the complex interactions between liver iron transport and iron homeostasis. This review outlines our current knowledge of molecules of iron metabolism and their roles in iron transport and regulation of iron homeostasis.
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Affiliation(s)
- Ross-M Graham
- School of Medicine and Pharmacology, Fremantle Hospital, University of Western Australia, PO Box 480, Fremantle 6959, Western Australia, Australia
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36
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Kim HJ, Kim HM, Kim JH, Ryu KS, Park SM, Jahng KY, Yang MS, Kim DH. Expression of heteropolymeric ferritin improves iron storage in Saccharomyces cerevisiae. Appl Environ Microbiol 2003; 69:1999-2005. [PMID: 12676675 PMCID: PMC154789 DOI: 10.1128/aem.69.4.1999-2005.2003] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Saccharomyces cerevisiae was engineered to express different amount of heavy (H)- and light (L)-chain subunits of human ferritin by using a low-copy integrative vector (YIp) and a high-copy episomal vector (YEp). In addition to pep4::HIS3 allele, the expression host strain was bred to have the selection markers leu2(-) and ura3(-) for YIplac128 and YEp352, respectively. The heterologous expression of phytase was used to determine the expression capability of the host strain. Expression in the new host strain (2805-a7) was as high as that in the parental strain (2805), which expresses high levels of several foreign genes. Following transformation, Northern and Western blot analyses demonstrated the expression of H- and L-chain genes. The recombinant yeast was more iron tolerant, in that transformed cells formed colonies on plates containing more than 25 mM ferric citrate, whereas none of the recipient strain cells did. Prussian blue staining indicated that the expressed isoferritins were assembled in vivo into a complex that bound iron. The expressed subunits showed a clear preference for the formation of heteropolymers over homopolymers. The molar ratio of H to L chains was estimated to be 1:6.8. The gel-purified heteropolymer took up iron faster than the L homopolymer, and it took up more iron than the H homopolymer did. The iron concentrations in transformants expressing the heteropolymer, L homopolymer, and H homopolymer were 1,004, 760, and 500 micro g per g (dry weight) of recombinant yeast cells, respectively. The results indicate that heterologously expressed H and L subunits coassemble into a heteropolymer in vivo and that the iron-carrying capacity of yeast is further enhanced by the expression of heteropolymeric isoferritin.
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Affiliation(s)
- Hye-Jin Kim
- Institute for Molecular Biology and Genetics. Basic Science Research Institute, Chonbuk National University, Chonju, Korea
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37
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Nielsen P, Engelhardt R, Düllmann J, Fischer R. Non-invasive liver iron quantification by SQUID-biosusceptometry and serum ferritin iron as new diagnostic parameters in hereditary hemochromatosis. Blood Cells Mol Dis 2002; 29:451-8. [PMID: 12547235 DOI: 10.1006/bcmd.2002.0583] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In the HFE-gene era, precise diagnostic parameters remain important to characterize individual iron stores, because the indication for therapy and prognosis are mainly related to the extent of iron loading. The frequently used serum ferritin interferes with non-iron related factors such as inflammation and may produce falsely positive values. We used a SQUID-biosusceptometer in a large series of patients (n = 679) to measure liver iron concentration in the differential diagnosis and therapy control of hereditary hemochromatosis (SQUID = superconducting quantum interference device). This truly non-invasive technique is sensitive, reliable, fast (online results), and also cost-effective when compared to invasive liver biopsy. Recently, ferritin iron content was propagated as a better parameter than ferritin protein. However, we found a poor correlation between ferritin iron and individual liver iron concentrations in patients with iron overload. Ferritin iron saturation varied in a range between 3 and 10%, independent from liver iron concentration. No differences were found between patients with hemochromatosis and secondary iron overload disease. Only patients with liver cell damage had increased ferritin iron saturations. In conclusion the diagnostic values of serum ferritin protein and iron to assess iron overload are limited.
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Affiliation(s)
- Peter Nielsen
- Inst. Molekulare Zellbiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
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38
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Nielsen P, Günther U, Dürken M, Fischer R, Düllmann J. Serum ferritin iron in iron overload and liver damage: correlation to body iron stores and diagnostic relevance. THE JOURNAL OF LABORATORY AND CLINICAL MEDICINE 2000; 135:413-8. [PMID: 10811057 DOI: 10.1067/mlc.2000.106456] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The iron content of serum ferritin has been determined in groups of patients with normal or increased iron stores by using a technique of ferritin immunoprecipitation followed by iron quantitation with atomic absorption spectroscopy. The results were correlated to individual liver iron concentrations, measured non-invasively by superconducting quantum interference device (SQUID) biomagnetometry. A close correlation between serum concentrations of ferritin protein and ferritin iron was found (r = 0.92) in all groups of patients. However, the correlation between ferritin iron concentration and individual liver iron concentration was poor in patients with hemochromatosis (r = 0.63) and patients with beta-thalassemia major (r = 0.57). The degree of ferritin iron saturation was about 5% in iron-loaded patients, which contrasts with results in two recent studies but confirms older observations. In patients with liver cell damage, the ferritin iron saturation in serum was significantly higher than that found in groups with iron overload disease, probably indicating the release of intracellular iron-rich ferritin into the blood. The monitoring of patients undergoing bone marrow transplantation indicated that the release of iron-rich and iron-poor ferritin occurred during phases of hepatocellular damage and inflammation, respectively. We find the benefits of serum ferritin iron measurement to be marginal in patients with iron overload disease.
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Affiliation(s)
- P Nielsen
- Department of Molecular Cell Biology, University Hospital of the University of Eppendorf, Hamburg, Germany
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39
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ten Kate J, Marell K, Huizinga R, Kreeftenberg H, van Deursen C. Iron saturation of ferritin in the course of phlebotomy treatment in patients with haemochromatosis. Clin Chem Lab Med 1999; 37:827-30. [PMID: 10536932 DOI: 10.1515/cclm.1999.124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
This paper describes the iron saturation of ferritin in haemochromatosis patients during phlebotomy therapy. The iron saturation of ferritin does not change during therapy and cannot be used as a parameter to follow therapy. Furthermore, the iron saturation seems to be a constant characteristic of a given person. It does not vary with the body iron stores in patients with haemochromatosis.
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Affiliation(s)
- J ten Kate
- Department of Clinical Chemistry, Atrium Medical Center, Heerlen/Brunssum, The Netherlands.
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40
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Analysis of Ferritins in Lymphoblastoid Cell Lines and in the Lens of Subjects With Hereditary Hyperferritinemia-Cataract Syndrome. Blood 1998. [DOI: 10.1182/blood.v91.11.4180.411k38_4180_4187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Hereditary hyperferritinemia-cataract syndrome (HHCS) is an autosomal and dominant disease caused by heterogeneous mutations in the iron responsive element (IRE) of the 5′ untranslated flanking region of ferritin L-chain mRNA, which reduce the binding to the trans iron regulatory proteins and make L-chain synthesis constitutively upregulated. In the several families identified so far, the serum and tissue L-ferritin levels are fivefold to 20-fold higher than in nonaffected control subjects, iron metabolism is apparently normal, and the only relevant clinical symptom is early onset, bilateral cataract. Some pathogenetic aspects of HHCS remain obscure, with particular reference to the isoferritins produced by HHCS cells, as well as the mechanism of cataract formation. We analyzed lymphoblastoid cell lines obtained from two nonaffected control subjects and from HHCS patients carrying the substitution A40G (Paris-1), G41C (Verona-1), and the deletion of the residues 10-38 (Verona-2) in the IRE structure. Enzyme-linked immunosorbent assays specific for the H- and L-type ferritins showed that L-ferritin levels were up to 20-fold higher in HHCS than in control cells and were not affected by iron supplementation or chelation. Sequential immunoprecipitation experiments of metabolically-labeled cells with specific antibodies indicated that in HHCS cells about half of the L-chain was assembled in L-chain homopolymers, which did not incorporate iron, and the other half was assembled in isoferritins with a high proportion of L-chain. In control cells, all ferritin was assembled in functional heteropolymers with equivalent proportion of H- and L-chains. Cellular and ferritin iron uptake was slightly higher in HHCS than control cells. In addition, we analyzed the lens recovered from cataract surgery of a HHCS patient. We found it to contain about 10-fold more L-ferritin than control lens. The ferritin was fully soluble with a low iron content. It was purified and partially characterized. Our data indicate that: (1) in HHCS cells a large proportion of L-ferritin accumulates as nonfunctional L-chain 24 homopolymers; (2) the concomitant fivefold to 10-fold expansion of ferritin heteropolymers, with a shift to L-chain–rich isoferritins, does not have major effects on cellular iron metabolism; (3) L-chain accumulation occurs also in the lens, where it may induce cataract formation by altering the delicate equilibrium between other water-soluble proteins (ie, crystallins) and/or the antioxidant properties.
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41
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Analysis of Ferritins in Lymphoblastoid Cell Lines and in the Lens of Subjects With Hereditary Hyperferritinemia-Cataract Syndrome. Blood 1998. [DOI: 10.1182/blood.v91.11.4180] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractHereditary hyperferritinemia-cataract syndrome (HHCS) is an autosomal and dominant disease caused by heterogeneous mutations in the iron responsive element (IRE) of the 5′ untranslated flanking region of ferritin L-chain mRNA, which reduce the binding to the trans iron regulatory proteins and make L-chain synthesis constitutively upregulated. In the several families identified so far, the serum and tissue L-ferritin levels are fivefold to 20-fold higher than in nonaffected control subjects, iron metabolism is apparently normal, and the only relevant clinical symptom is early onset, bilateral cataract. Some pathogenetic aspects of HHCS remain obscure, with particular reference to the isoferritins produced by HHCS cells, as well as the mechanism of cataract formation. We analyzed lymphoblastoid cell lines obtained from two nonaffected control subjects and from HHCS patients carrying the substitution A40G (Paris-1), G41C (Verona-1), and the deletion of the residues 10-38 (Verona-2) in the IRE structure. Enzyme-linked immunosorbent assays specific for the H- and L-type ferritins showed that L-ferritin levels were up to 20-fold higher in HHCS than in control cells and were not affected by iron supplementation or chelation. Sequential immunoprecipitation experiments of metabolically-labeled cells with specific antibodies indicated that in HHCS cells about half of the L-chain was assembled in L-chain homopolymers, which did not incorporate iron, and the other half was assembled in isoferritins with a high proportion of L-chain. In control cells, all ferritin was assembled in functional heteropolymers with equivalent proportion of H- and L-chains. Cellular and ferritin iron uptake was slightly higher in HHCS than control cells. In addition, we analyzed the lens recovered from cataract surgery of a HHCS patient. We found it to contain about 10-fold more L-ferritin than control lens. The ferritin was fully soluble with a low iron content. It was purified and partially characterized. Our data indicate that: (1) in HHCS cells a large proportion of L-ferritin accumulates as nonfunctional L-chain 24 homopolymers; (2) the concomitant fivefold to 10-fold expansion of ferritin heteropolymers, with a shift to L-chain–rich isoferritins, does not have major effects on cellular iron metabolism; (3) L-chain accumulation occurs also in the lens, where it may induce cataract formation by altering the delicate equilibrium between other water-soluble proteins (ie, crystallins) and/or the antioxidant properties.
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Corsi B, Perrone F, Bourgeois M, Beaumont C, Panzeri MC, Cozzi A, Sangregorio R, Santambrogio P, Albertini A, Arosio P, Levi S. Transient overexpression of human H- and L-ferritin chains in COS cells. Biochem J 1998; 330 ( Pt 1):315-20. [PMID: 9461525 PMCID: PMC1219142 DOI: 10.1042/bj3300315] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The understanding of the in vitro mechanisms of ferritin iron incorporation has greatly increased in recent years with the studies of recombinant and mutant ferritins. However, little is known about how this protein functions in vivo, mainly because of the lack of cellular models in which ferritin expression can be modulated independently from iron. To this aim, primate fibroblastoid COS-7 cells were transiently transfected with cDNAs for human ferritin H- and L-chains under simian virus 40 promoter and analysed within 66 h. Ferritin accumulation reached levels 300-500-fold higher than background, with about 40% of the cells being transfected. Thus ferritin concentration in individual cells was increased up to 1000-fold over controls with no evident signs of toxicity. The exogenous ferritin subunits were correctly assembled into homopolymers, but did not affect either the size or the subunit composition of the endogenous heteropolymeric fraction of ferritin, which remained essentially unchanged in the transfected and non-transfected cells. After 18 h of incubation with [59Fe]ferric-nitrilotriacetate, cellular iron incorporation was similar in the transfected and non-transfected cells and most of the protein-bound radioactivity was associated with ferritin heteropolymers, while H- and L-homopolymers remained iron-free. Cell co-transfection with cDNAs for H- and L-chains produced ferritin heteropolymers that also did not increase cellular iron incorporation. It is concluded that transient transfection of COS cells induces a high level of expression of ferritin subunits that do not co-assemble with the endogenous ferritins and have no evident activity in iron incorporation/metabolism.
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Affiliation(s)
- B Corsi
- Dibit, Institute H.San Raffaele, Via Olgettina 58, 20132 Milan, Italy
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ten Kate J, Wolthuis A, Westerhuis B, van Deursen C. The iron content of serum ferritin: physiological importance and diagnostic value. EUROPEAN JOURNAL OF CLINICAL CHEMISTRY AND CLINICAL BIOCHEMISTRY : JOURNAL OF THE FORUM OF EUROPEAN CLINICAL CHEMISTRY SOCIETIES 1997; 35:53-6. [PMID: 9156568 DOI: 10.1515/cclm.1997.35.1.53] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
In this paper we present a method for determining the iron saturation of ferritin as a possible independent predictor of iron stores. Serum ferritin was purified by immunochemical precipitation, and could be completely recovered from serum without any contamination from transferrin. The iron content of the precipitated ferritin was determined by flameless atomic absorption spectrophotometry (FAAS) and the ferritin-iron saturation was calculated using the original serum ferritin concentration. The intra- and inter-assay variation coefficients were 4.2% and 13.4% respectively. The first results with this assay indicate that serum ferritin contains a considerable amount of iron. Furthermore the results show that the iron saturation of ferritin in patients with acute phase response is significantly lower than the saturation found in healthy volunteers (19.3% and 24.3% respectively). These results suggest a possible role for the ferritin-iron saturation in the assessment of iron stores in patients suffering from acute phase response. In addition, the considerable amount of iron in ferritin suggests the need to revise the physiological role of this substance in relation to the serum iron homeostasis.
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Affiliation(s)
- J ten Kate
- Department of Clinical Chemistry, De Wever and Gregorius Hospital, Heerlen, Brunssum, The Netherlands
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44
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Harrison PM, Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation. BIOCHIMICA ET BIOPHYSICA ACTA 1996; 1275:161-203. [PMID: 8695634 DOI: 10.1016/0005-2728(96)00022-9] [Citation(s) in RCA: 1844] [Impact Index Per Article: 63.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The iron storage protein, ferritin, plays a key role in iron metabolism. Its ability to sequester the element gives ferritin the dual functions of iron detoxification and iron reserve. The importance of these functions is emphasised by ferritin's ubiquitous distribution among living species. Ferritin's three-dimensional structure is highly conserved. All ferritins have 24 protein subunits arranged in 432 symmetry to give a hollow shell with an 80 A diameter cavity capable of storing up to 4500 Fe(III) atoms as an inorganic complex. Subunits are folded as 4-helix bundles each having a fifth short helix at roughly 60 degrees to the bundle axis. Structural features of ferritins from humans, horse, bullfrog and bacteria are described: all have essentially the same architecture in spite of large variations in primary structure (amino acid sequence identities can be as low as 14%) and the presence in some bacterial ferritins of haem groups. Ferritin molecules isolated from vertebrates are composed of two types of subunit (H and L), whereas those from plants and bacteria contain only H-type chains, where 'H-type' is associated with the presence of centres catalysing the oxidation of two Fe(II) atoms. The similarity between the dinuclear iron centres of ferritin H-chains and those of ribonucleotide reductase and other proteins suggests a possible wider evolutionary linkage. A great deal of research effort is now concentrated on two aspects of ferritin: its functional mechanisms and its regulation. These form the major part of the review. Steps in iron storage within ferritin molecules consist of Fe(II) oxidation, Fe(III) migration and the nucleation and growth of the iron core mineral. H-chains are important for Fe(II) oxidation and L-chains assist in core formation. Iron mobilisation, relevant to ferritin's role as iron reserve, is also discussed. Translational regulation of mammalian ferritin synthesis in response to iron and the apparent links between iron and citrate metabolism through a single molecule with dual function are described. The molecule, when binding a [4Fe-4S] cluster, is a functioning (cytoplasmic) aconitase. When cellular iron is low, loss of the [4Fe-4S] cluster allows the molecule to bind to the 5'-untranslated region (5'-UTR) of the ferritin m-RNA and thus to repress translation. In this form it is known as the iron regulatory protein (IRP) and the stem-loop RNA structure to which it binds is the iron regulatory element (IRE). IREs are found in the 3'-UTR of the transferrin receptor and in the 5'-UTR of erythroid aminolaevulinic acid synthase, enabling tight co-ordination between cellular iron uptake and the synthesis of ferritin and haem. Degradation of ferritin could potentially lead to an increase in toxicity due to uncontrolled release of iron. Degradation within membrane-encapsulated "secondary lysosomes' may avoid this problem and this seems to be the origin of another form of storage iron known as haemosiderin. However, in certain pathological states, massive deposits of "haemosiderin' are found which do not arise directly from ferritin breakdown. Understanding the numerous inter-relationships between the various intracellular iron complexes presents a major challenge.
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Affiliation(s)
- P M Harrison
- Krebs Institute, Department of Molecular Biology and Biotechnology, University of Sheffield, UK
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Wigginton JM. Reversal of ferritin-mediated immunosuppression by levamisole: a rationale for its application to management of the acquired immune deficiency syndrome (AIDS). Med Hypotheses 1995; 44:85-8. [PMID: 7596311 DOI: 10.1016/0306-9877(95)90075-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Ferritin is a complex polypeptide which functions primarily as an iron-storage protein. Ferritin may also play a role in the modulation of immune function. It is known to suppress several global measures of the immune response. Specifically, ferritin may mask and/or down-regulate expression of cell surface molecules important in T-cell activation and effector functions. These interactions may become pathologically significant in conditions where marked hyperferritinemia occurs, most notably malignancies and the acquired immunodeficiency syndrome (AIDS). Levamisole appears to possess immunomodulatory properties and be capable of disrupting the interaction of ferritin with T lymphocytes. This activity may be therapeutically useful in conditions of ferritin excess, such as progressive human immunodeficiency virus (HIV) infection and its associated opportunistic complications.
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Tacchini L, Rappocciolo E, Ferrero M, Schiaffonati L, Cairo G. Ferritin mRNAs on rat liver membrane-bound polysomes synthesize ferritin that does not translocate across membranes. BIOCHIMICA ET BIOPHYSICA ACTA 1992; 1131:133-8. [PMID: 1610892 DOI: 10.1016/0167-4781(92)90067-a] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Ferritin is a typical intracellular protein but small amounts are also present in serum and other biological fluids. The source and physiological significance of serum ferritin are still obscure. The presence of ferritin mRNAs on polysomes bound to endoplasmic reticulum (ER) could be relevant for the secretion of ferritin. By Northern blot analysis we found significant amounts of both L and H subunit mRNAs on rat liver membrane-bound polysomes. Immunoprecipitation of translational products of membrane-bound polysomes with anti-rat liver ferritin antibody showed that ferritin is actually synthesized on ER membranes. Analysis of RNA extracted from salt-washed rat liver microsomes demonstrated that ferritin mRNAs are translated by polysomes tightly bound to ER membranes. Following iron treatment, both the amount of H and L subunit mRNAs and ferritin synthesis increased sharply in both free and bound polysomal fractions. Translation of membrane-bound polysomes in the presence of microsomal membranes indicated that ferritin is not processed by signal sequence cleavage or glycosylation and is not translocated into ER membranes. Ferritin mRNAs found on membrane-bound polysomes are associated with ER in a specific way, however, their products do not seem to follow the classic secretory pathway and therefore the significance of the large amount of ferritin mRNAs in the bound ribosome fraction remains unclear.
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Affiliation(s)
- L Tacchini
- Istituto di Patologia Generale, Università degli Studi, Italy
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Wade VJ, Levi S, Arosio P, Treffry A, Harrison PM, Mann S. Influence of site-directed modifications on the formation of iron cores in ferritin. J Mol Biol 1991; 221:1443-52. [PMID: 1942061 DOI: 10.1016/0022-2836(91)90944-2] [Citation(s) in RCA: 113] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The structure and crystal chemical properties of iron cores of reconstituted recombinant human ferritins and their site-directed variants have been studied by transmission electron microscopy and electron diffraction. The kinetics of Fe uptake have been compared spectrophotometrically. Recombinant L and H-chain ferritins, and recombinant H-chain variants incorporating modifications in the threefold (Asp131----His or Glu134----Ala) and fourfold (Leu169----Arg) channels, at the partially buried ferroxidase sites (Glu62,His65----Lys,Gly), a putative nucleation site on the inner surface (Glu61,Glu64,Glu67----Ala), and both the ferroxidase and nucleation sites (Glu62,His65----Lys,Gly and Glu61,Glu64,Glu67----Ala), were investigated. An additional H-chain variant, incorporating substitution of the last ten C-terminal residues for those of the L-chain protein, was also studied. Most of the proteins assimilated iron to give discrete electron-dense cores of the Fe(III) hydrated oxide, ferrihydrite (Fe2O3.nH2O). No differences were observed for variants modified in the three- or fourfold channels compared with the unmodified H-chain ferritin. The recombinant L-chain ferritin and H-chain variant depleted of the ferroxidase site, however, showed markedly reduced uptake kinetics and comprised cores of increased diameter and regularity. Depletion of the inner surface Glu residues, whilst maintaining the ferroxidase site, resulted in a partially reduced rate of Fe uptake and iron cores of wider particle size distribution. Modification of both ferroxidase and inner surface Glu residues resulted in complete inhibition of iron uptake and deposition. No cores were observed by electron microscopy although negative staining showed that the protein shell was intact. The general requirement of an appropriate spatial charge density across the cavity surface rather than specific amino acid residues could explain how, in spite of an almost complete lack of identity between the amino acid sequences of bacterioferritin and mammalian ferritins, ferrihydrite is deposited within the cavity of both proteins under similar reconstitution conditions.
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Affiliation(s)
- V J Wade
- School of Chemistry, University of Bath, U.K
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Lasne Y, Francina A, Benzerara O. Serum ferritin spectrotypes in patients with heterozygous beta-thalassaemia. Clin Chim Acta 1991; 197:85-93. [PMID: 2049859 DOI: 10.1016/0009-8981(91)90270-m] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Serum ferritin spectrotypes from patients heterozygous for beta-thalassaemia were determined after agarose isoelectric focusing followed by radio-immunofixation with anti-ferritin antibody. Multivariate analysis demonstrated a specific spectrotype for heterozygous beta-thalassaemia. This spectrotype was shown to be different from those in hereditary spherocytosis and idiopathic haemochromatosis. Statistical discrimination reached 100% of well-classified patients between these pathological conditions.
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Affiliation(s)
- Y Lasne
- Laboratoire Central des Isotopes, Hôpital Edouard Herriot, Lyon, France
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Abstract
Over the last 10 years there has been steady progress in our understanding of the structure of the iron-binding proteins transferrin and ferritin, and the transferrin receptor. In the last few years there have been very rapid developments in understanding of the genetics of these proteins and the regulation of synthesis. This review includes a description of gene localization and structure, the regulation of protein synthesis and the structure of proteins of the transferrin family, the transferrin receptor and the iron storage protein ferritin.
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Affiliation(s)
- M Worwood
- Department of Haematology, University of Wales College of Medicine, Heath Park, Cardiff, UK
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Mechanism of ferritin iron uptake: activity of the H-chain and deletion mapping of the ferro-oxidase site. A study of iron uptake and ferro-oxidase activity of human liver, recombinant H-chain ferritins, and of two H-chain deletion mutants. J Biol Chem 1988. [DOI: 10.1016/s0021-9258(19)81326-1] [Citation(s) in RCA: 275] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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