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      The role of hepcidin, GDF15, and mitoferrin-1 in iron metabolism of polycythemia vera and essential thrombocytosis patients

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          Abstract

          Background/aim

          GDF15, hepcidin and mitoferrin-1 (mfrn-1) are proteins involved in systemic iron regulation. There are no studies in the literature demonstrating the serum mfrn-1 levels in polycythemia vera (PV) and essential thrombocythemia (ET) patients. The aim of this study was to investigate GDF15, hepcidin and mfrn-1 levels in PV and ET patients.

          Materials and methods

          Ten PV, 17 ET patients, and 27 healthy controls (HCs) were enrolled. GDF15, hepcidin and mfrn-1 values were measured with enzyme-linked immunosorbent assay (ELISA).

          Results

          GDF15 levels were higher in the myeloproliferative neoplasm (MPN) group (P = 0.002). Hepcidin levels were not different between MPN patients and HCs. The mfrn-1 levels were lower in MPN patients (P = 0.039). Hepcidin, GDF15, and mfrn-1 levels were not different between PV and ET patients. mfrn-1 levels were lower in ET patients than HCs (P = 0.038).

          Conclusion

          Increased erythropoiesis in MPNs may lead to high GDF15 levels in these patients. However, hepcidin was not suppressed despite the increased GDF15 levels and erythropoiesis in these patients. Decrease in mfrn-1 in MPNs can be the result of its increased turnover due to increased myelopoiesis. It can be hypothesized that similar hepcidin levels in patients and controls and low mfrn-1 levels in patients may be a defense mechanism against erythroid activity and thromboembolic complications.

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          Most cited references20

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          Mitoferrin is essential for erythroid iron assimilation.

          Iron has a fundamental role in many metabolic processes, including electron transport, deoxyribonucleotide synthesis, oxygen transport and many essential redox reactions involving haemoproteins and Fe-S cluster proteins. Defective iron homeostasis results in either iron deficiency or iron overload. Precise regulation of iron transport in mitochondria is essential for haem biosynthesis, haemoglobin production and Fe-S cluster protein assembly during red cell development. Here we describe a zebrafish mutant, frascati (frs), that shows profound hypochromic anaemia and erythroid maturation arrest owing to defects in mitochondrial iron uptake. Through positional cloning, we show that the gene mutated in the frs mutant is a member of the vertebrate mitochondrial solute carrier family (SLC25) that we call mitoferrin (mfrn). mfrn is highly expressed in fetal and adult haematopoietic tissues of zebrafish and mouse. Erythroblasts generated from murine embryonic stem cells null for Mfrn (also known as Slc25a37) show maturation arrest with severely impaired incorporation of 55Fe into haem. Disruption of the yeast mfrn orthologues, MRS3 and MRS4, causes defects in iron metabolism and mitochondrial Fe-S cluster biogenesis. Murine Mfrn rescues the defects in frs zebrafish, and zebrafish mfrn complements the yeast mutant, indicating that the function of the gene may be highly conserved. Our data show that mfrn functions as the principal mitochondrial iron importer essential for haem biosynthesis in vertebrate erythroblasts.
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            JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin.

            Erythropoietin (EPO) regulates the proliferation and differentiation of erythroid cells through interaction with its receptor (EPOR). Although EPOR is a member of the cytokine receptor superfamily and lacks a kinase domain, EPO induces tyrosine phosphorylation, which is correlated with gene transcription and mitogenesis. Here we demonstrate that EPO induces tyrosine phosphorylation of JAK2 kinase and activates its in vitro autophosphorylation. Using EPOR mutants, phosphorylation and activation of kinase activity correlate with the induction of mitogenesis. Furthermore, JAK2 physically associates with a membrane-proximal region of the EPOR cytoplasmic domain that is required for biological activity. The results support the hypothesis that JAK2 is the kinase that couples EPO binding to tyrosine phosphorylation and mitogenesis.
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              Regulation of mitochondrial iron import through differential turnover of mitoferrin 1 and mitoferrin 2.

              Mitoferrin 1 and mitoferrin 2 are homologous members of the mitochondrial solute carrier family. Mitoferrin 1 is required for mitochondrial iron delivery in developing erythrocytes. Here we show that mitoferrin 1 and mitoferrin 2 contribute to mitochondrial iron delivery in a variety of cells. Reductions in mitoferrin 1 and/or mitoferrin 2 levels by RNA interference result in decreased mitochondrial iron accumulation, heme synthesis, and iron-sulfur cluster synthesis. The ectopic expression of mitoferrin 1 in nonerythroid cells silenced for mitoferrin 2 or the expression of mitoferrin 2 in cells silenced for mitoferrin 1 restored heme synthesis to "baseline" levels. The ectopic expression of mitoferrin 2, however, did not support hemoglobinization in erythroid cells deficient in mitoferrin 1. Mitoferrin 2 could not restore heme synthesis in developing erythroid cells because of an inability of the protein to accumulate in mitochondria. The half-life of mitoferrin 1 was increased in developing erythroid cells, while the half-life of mitoferrin 2 did not change. These results suggest that mitochondrial iron accumulation is tightly regulated and that controlling mitoferrin levels within the mitochondrial membrane provides a mechanism to regulate mitochondrial iron levels.
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                Author and article information

                Journal
                Turk J Med Sci
                Turk J Med Sci
                Turkish Journal of Medical Sciences
                The Scientific and Technological Research Council of Turkey
                1300-0144
                1303-6165
                2019
                11 February 2019
                : 49
                : 1
                : 74-80
                Affiliations
                [1 ] Department of Internal Medicine, School of Medicine, Kocaeli University, Kocaeli Turkey
                [2 ] Department of Hematology, School of Medicine, Kocaeli University, Kocaeli Turkey
                [3 ] Department of Biochemistry, School of Medicine, Kocaeli University, Kocaeli Turkey
                Author notes
                * To whom correspondence should be addressed. E-mail: pinartarkun@ 123456hotmail.com

                CONFLICT OF INTEREST:

                none declared

                Author information
                https://orcid.org/0000-0001-5938-8044
                https://orcid.org/0000-00003-0851-3583
                https://orcid.org/0000-0002-2596-4493
                https://orcid.org/0000-0002-6710-538X
                https://orcid.org/0000-0002-6710-538X
                https://orcid.org/0000-0001-7083-9379
                https://orcid.org/0000-0002-5603-1178
                https://orcid.org/0000-0001-9556-8915
                https://orcid.org/0000-0001-5164-6301
                Article
                10.3906/sag-1803-13
                7350842
                30761871
                7a9412e1-483f-4fa0-ad87-a7a1854f5ec0
                Copyright © 2019 The Author(s)

                This article is distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                Categories
                Article

                polycythemia vera, essential thrombocythemia, chronic myeloproliferative neoplasm, gdf15, hepcidin, mitoferrin-1

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