Erythroferrone as erythroid regulator of iron
A. V. Budnevskiy,
L. N. Tsvetikova,
E. V. Voronina,
E. S. Ovsyannikov,
Yu. G. Zhusina,
N. B. Labzhaniya https://doi.org/10.18821/0234-5730-2016-61-3-161-163
Abstract
Iron is an essential element of the cell activity. The most important role of iron is determined by the functions of proteins that contain this metal: hemoglobin and myoglobin that execute the transport and storage of oxygen; enzymes involved in the processes of biological oxidation (cytochrome p450), various peroxidases and catalase supporting redox balance. Iron metabolism being unique process is regulated by a number of proteins, providing a narrow safe range of iron content in the cells. 25-amino acid protein hepcidin in the past 10 years was considered to be a key regulator of iron metabolism. Hepcidin controls main streams of the iron distribution: the absorption of nutritional iron in the intestine, utilization of its macrophages phagocyting old red blood cells, and iron mobilization from hepatocytes. In the literature there is occurred sometimes the term “erythroid regulator of iron metabolism”, however, for the long time the desired protein remained elusive. Proposed erythroid regulator should ensure the delivery of iron to the bone marrow due to suppression of blood expression of hepcidin, thereby increasing the absorption of iron from enterocytes and stimulating the release of its stock. In recent studies there were proved properties of myonectin as a regulator of erythroid iron. Subsequently, this myokine was renamed as erythroferrone. As distinct from the adaptive role erythroferrone may contribute to the iron overload in patients with severe hereditary anemias and in patients receiving frequent blood transfusions. In this paper, we present a brief discussion of functions of erythroferrones, as well as the transferrin receptor 2, and their role in iron metabolism.
About the Authors
A. V. Budnevskiy
Voronezh State Medical University named after N.N. Burdenko
Russian Federation
Voronezh, 394000
Russian Federation
Voronezh, 394000
L. N. Tsvetikova
Voronezh State Medical University named after N.N. Burdenko
Russian Federation
Voronezh, 394000
Russian Federation
Voronezh, 394000
E. V. Voronina
Voronezh State Medical University named after N.N. Burdenko
Russian Federation
Voronezh, 394000
Russian Federation
Voronezh, 394000
E. S. Ovsyannikov
Voronezh State Medical University named after N.N. Burdenko
Russian Federation
Russian Federation
Ovsyannikov Evgeny S., MD, PhD, associate professor
Voronezh, 394000
Yu. G. Zhusina
Voronezh State Medical University named after N.N. Burdenko
Russian Federation
Voronezh, 394000
Russian Federation
Voronezh, 394000
N. B. Labzhaniya
Voronezh State Medical University named after N.N. Burdenkо
Russian Federation
Voronezh, 394000
Russian Federation
Voronezh, 394000
References
1. Lawen A., Lane D.J. Mammalian iron homeostasis in health and disease: uptake, storage, transport, and molecular mechanisms of action. Antioxid. Redox. Signal. 2013; 18(18): 2473—507.
2. Chua A.C., Graham R.M., Trinder D., Olynyk J.K. The regulation of cellular iron metabolism. Crit. Rev. Clin. Lab. Sci. 2007; 44(5–6): 413–59
3. Hentze M.W., Muckenthaler M.U., Andrews N.C. Balancingacts: molecular control of mammalian iron metabolism. Cell. 2004; 117(3): 285–97.
4. Torti F.M., Torti S.V. Regulation of ferritin genes and protein. Blood. 2002; 99(10): 3505–16.
5. Gomme P.T., McCann K.B., Bertolini J. Transferrin: structure, function and potential therapeutic actions. Drug. Discov. Today. 2005; 10(4): 267–73.
6. Wally J., Halbrooks P.J., Vonrhein C., Rould M.A., Everse S.J., Mason A.B., et al. The crystal structure of iron-free human serum ransferring provides insight intointer-lobe communication and receptor binding. J. Biol. Chem. 2006; 281(34): 24934–44.
7. Fleming M.D., Trenor C.C., Su M.A., Foernzler D., Beier D.R., Dietrich W.F., et al. Microcytic anaemia micehave a mutation in Nramp2, a candidate iron transporter gene. Nat. Genet. 1997; 16(4): 383–6.
8. Fleming M.D., Romano M.A., Su M.A., Garrick L.M., Garrick M.D., Andrews N.C. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron F transport. Proc. Nat. L. Acad. Sci. USA 1998; 95(3): 1148–53.
9. Kristiansen M., Graversen J.H., Jacobsen C., Sonne O., Hoffman H.J., Law S.K., et al. Identificationof the haemoglobin scavenger receptor.Nature. 2001; 409(6817): 198–201.
10. Krause A., Neitz S., Magert H.J., Schulz A., Forssmann W.G., SchulzKnappe P., Adermann K. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000; 480(2–3): 147–50.
11. Park C.H., Valore E.V., Waring A.J., Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J. Biol. Chem. 2001; 276(11): 7806–10.
12. Andrews P. A. Disorders of iron metabolism. N. Engl. J. Med. 2000; 342(17): 1293.
13. Meynard D., Kautz L., Darnaud V., Canonne-Hergaux F., Coppin H., Roth M.P. Lack of the bone morphogenetic protein BMP6 inducesmassive iron overload. Nat. Genet. 2009; 41(4): 478–81.
14. Andriopoulos B., Corradini E., Xia Y., Faasse S.A., Chen S., Grgurevic L., et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat. Genet. 2009; 41(4): 482–7.
15. Babitt J.L., Huang F.W., Wrighting D.M., Xia Y., Sidis Y., Samad T.A., et al. Bone morphogeneticprotein signaling by hemojuvelin regulates hepcidin expression. Nat. Genet. 2006; 38(5): 531–9.
16. Pietrangelo A., Dierssen U., Valli L., Garuti C., Rump A., Corradini E., et al. STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology, 2007; 132(1): 294–300.
17. Sakamori R., Takehara T., Tatsumi T., Shigekawa M., Hikita H., Hiramatsu N., et al. STAT3 signaling withinhepatocytes is required for anemia of inflammation in vivo. J. Gastroenterol. 2010; 45(2): 244–8.
18. Wrighting D.M., Andrews N.C. Interleukin-6 induces hepcidin expression through STAT3. Blood. 2006; 108(9): 3204–9.
19. Verga Falzacappa M.V., Vujic Spasic M., Kessler R., Stolte J., Hentze M.W., Muckenthaler M.U. STAT3 mediates hepatic hepcidin expressionand its inflammatory stimulation. Blood. 2007; 109(1): 353–8.
20. Lin L., Valore E.V., Nemeth E., Goodnough J.B., Gabayan V., Ganz T. Irontransferrin regulates hepcidin synthesis in primary hepatocyte culturethrough hemojuvelin and BMP2/4. Blood. 2007; 110(6): 2182–9.
21. Steinbicker A.U., Sachidanandan C., Vonner A.J., Yusuf R.Z., Deng D.Y., Lai C.S., et al. Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation. Blood 2011; 117(18): 4915–23.
22. Theurl I., Schroll A., Sonnweber T., Nairz M., Theurl M., Willenbacher W., et al. Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats. Blood. 2011; 118(18): 4977–84. doi: 10.1182/blood-2011-03-345066.
23. Ganz T., Nemeth E. Hepcidin and iron homeostasis. Biochim. Biophys. Acta. 2012; 1823(9): 1434–43.
24. Pak M., Lopez M.A., Gabayan V., Ganz T., Rivera S. Suppression of hepcidin during anemia requires erythropoietic activity. Blood. 2006; 108(12): 3730–5.
25. Vokurka M., Krijt J., Sulc K., Necas E. Hepcidin mRNA levels in mouse liver respond to inhibition of erythropoiesis. Physiol. Res. 2006; 55(6): 667–74.
26. Ashby D.R., Gale D.P., Busbridge M., Murphy K.G., Duncan N.D., Cairns T.D., et al. Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin. Haematologica. 2010; 95(3): 505–8. doi: 10.3324/haematol.2009.013136.
27. Tanno T., Bhanu N.V., Oneal P.A., Goh S.H., Staker P., Lee Y.T., et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat. Med. 2007; 13(9): 1096–101.
28. Tanno T., Porayette P., Sripichai O., Noh S.J., Byrnes C., Bhupatiraju A., et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood. 2009; 114(1): 181–6.
29. Santini V., Girelli D., Sanna A., Martinelli N., Duca L., Campostrini N., et al. Hepcidin levels and their determinants in different types of myelodysplastic syndromes. PLoS. One. 2011; 6(8): e23109.
30. Cazzola M., Beguin Y., Bergamaschi G., Guarnone R., Cerani P., Barella S., et al. Soluble ransferring receptor as a potential determinant of iron loading in congenital anaemias due to ineffective erythropoiesis. Br. J. Haematol. 1999; 106(3): 752–5.
31. Flanagan J.M., Peng H., Wang L., Gelbart T., Lee P., Johnson Sasu B., Beutler E. Soluble ransferring receptor-1 levels in mice do not affect iron absorption. Acta Haematol. 2006; 116(4): 249–54.
32. Ramos P., Melchiori L., Gardenghi S., Van-Roijen N., Grady R.W., Ginzburg Y., Rivella S. Iron metabolism and ineffective erythropoiesis in beta-thalassemia mouse models. Ann. N.Y. Acad. Sci. 2010; 1202: 24–30. doi: 10.1111/j.1749-6632.2010.05596.x.
33. Kautz L., Jung G., Valore E.V., Rivella S., Nemeth E., Ganz T. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat. Genet. 2014; 46(7): 678–84.
34. Kautz L., Jung G., Nemeth E., Ganz T. Erythroferrone contributes to recovery from anemia of inflammation. Blood. 2014; 124(16): 2569–74.
35. Seldin M.M., Peterson J.M., Byerly M.S., Wei Z., Wong G.W. Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis. J. Biol. Chem. 2012; 287(15): 11968–80. doi: 10.1074/jbc.M111.336834.
36. Park S.Y., Choi J.H., Ryu H.S., Pak Y.K., Park K.S., Lee H.K., Lee W. C1q tumor necrosis factor alpha-related protein isoform 5 is increased in mitochondrial DNA-depleted myocytes and activates AMP-activated protein kinase. J. Biol. Chem. 2009; 284(41): 27780–9.
37. Gunga H.C., Kirsch K.A., Roecker L., Kohlberg E., Tiedemann J., Steinach M., Schobersberger W. Erythropoietin regulations in humans under different environmental and experimental conditions. Respir. Physiol. Neurobiol. 2007; 158(2–3): 287–97.
38. Wallace D.F., Secondes E.S., Rishi G., Ostini L., McDonald C.J., Lane S.W., et al. A critical role for murine ransferring receptor 2 in erythropoiesis during iron restriction. Br. J. Haematol. 2015; 168(6): 891–901.
39. Nai A., Pellegrino R.M., Rausa M., Pagani A., Boero M., Silvestri L., et al. The erythroid function of ransferring receptor 2 revealed by Tmprss6 inactivation in different models of ransferring receptor 2 knockout mice. Haematologica. 2014; 99(6): 1016–21.
40. Lane D.J., Lawen A. Non-transferrin iron reduction and uptake are regulated by transmembrane ascorbate cycling in K562 cells. J. Biol. Chem. 2008; 283(3): 12701–8.
Review
For citations:
Budnevskiy A.V., Tsvetikova L.N., Voronina E.V., Ovsyannikov E.S., Zhusina Yu.G., Labzhaniya N.B. Erythroferrone as erythroid regulator of iron. Russian journal of hematology and transfusiology. 2016;61(3):161-163. (In Russ.) https://doi.org/10.18821/0234-5730-2016-61-3-161-163
Views:
771
Email this article 
