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Molecular Medicine Partnership UnitResearch Groups

Iron homeostasis in health and disease

Matthias W. Hentze and Martina Muckenthaler

Matthias Hentze and Martina Muckenthaler

Project Summary

As an essential nutrient and a potential toxin, iron poses an exquisite regulatory problem in biology and medicine. Disturbances of the delicate balancing systems for systemic and/or local iron homeostasis are emerging as underlying causes of common hematological, metabolic and neurodegenerative diseases. Our research aims to understand the physiological control of cellular and systemic iron metabolism and its disturbances in human disease

Background

Iron is essential for fundamental metabolic processes in cells and organisms. Regulation of systemic iron homeostasis evolved to maintain a plasma iron concentration that secures adequate supplies while preventing organ iron overload. The homeostatic system must react to signals from pathways that consume iron (e.g. the erythropoiesis) and send signals to cells that supply iron (e.g. duodenal enterocytes, which absorb iron from the diet; macrophages which recycle iron from senescent erythrocytes, and hepatocytes which are the major iron stores). The small hepatic peptide hormone hepcidin (Hamp, LEAP1) orchestrates these iron fluxes and controls the amount of available extracellular iron by interacting with the iron exporter ferroportin: binding of hepcidin induces ferroportin internalization and degradation.

Goals

Recent research started to move towards network/systems-based analysis of iron metabolism by integrating DNA microarray approaches, mouse models and high through-put siRNA screens. The overall aim is a more detailed understanding of regulatory mechanisms involved in iron homeostasis and the identification of novel regulators of iron metabolism. We then aim to translate new results into understanding human disease and to contribute to clinical patient management.

Specifically, we plan to investigate three themes:

  1. molecular mechanisms underlying hereditary hemochromatosis;
  2. signalling pathways underlying hepcidin regulation and
  3. the hepcidin/ferroportin regulatory system.

Research Focus 1: Hereditary hemochromatosis

One research focus of our lab aims to investigate molecular mechanisms underlying hereditary hemochromatosis. Using conditional Hfe knock-out mouse lines we will investigate hepatic as well as extra-hepatic functions of the broadly expressed Hfe protein.
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Research Focus 2: Hepcidin regulation

We further focus on the identification of signalling pathways underlying hepcidin regulation. High-throughput siRNA screening is applied to identify novel regulators of hepcidin expression.
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Research Focus 3: Hepcidin-mediated ferroportin regulation 

A third research focus is on the identification of molecular mechanisms that control hepcidin-mediated ferroportin regulation.
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Selected publications.

Resistance of Ferroportin to Hepcidin Binding causes Exocrine Pancreatic Failure and Fatal Iron Overload.
Altamura S, Kessler R, Gröne HJ, Gretz N, Hentze MW, Galy B, Muckenthaler MU.
Cell Metab. 2014 Aug 5;20(2):359-67. doi: 10.1016

Novel activating mutations lacking cysteine in type I cytokine receptors in acute lymphoblastic leukemia.
Shochat C1, Tal N, Gryshkova V, Birger Y, Bandapalli OR, Cazzaniga G, Gershman N, Kulozik AE, Biondi A, Mansour MR, Twizere JC, Muckenthaler MU, Ben-Tal N, Constantinescu SN, Bercovich D, Izraeli S.
Blood. 2014 Jul 3;124(1):106-10

Atherogenesis and iron: from epidemiology to cellular level.
Vinchi F, Muckenthaler MU, Da Silva MC, Balla G, Balla J, Jeney V.
Front Pharmacol. 2014 May 5;5:94. doi: 10.3389/fphar.2014.00094. eCollection 2014. Review

Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to the proliferative Ras/RAF and the nutrient-dependent mTOR signaling pathways.
Mleczko-Sanecka, K., F. Roche, A.R. da Silva, D. Call, F. D’Allesio, A. Ragab, P.E. Lapinski, R. Ummanni, U. Korf, C. Oakes, G. Damm, L.A. D’Alessandro, U. Klingmüller, P.D. King, M. Boutros, M.W. Hentze and M.U. Muckenthaler. 
Blood. 2014 Mar 6;123(10):1574-85. doi: 10.1182/blood-2013-07-515957. Epub 2014 Jan 2.

Comparison of different IRT-PAP protocols to screen newborns for cystic fibrosis in three central European populations.
Sommerburg O, Krulisova V, Hammermann J, Lindner M, Stahl M, Muckenthaler M, Kohlmueller D, Happich M, Kulozik AE, Votava F, Balascakova M, Skalicka V, Stopsack M, Gahr M, Macek M Jr, Mall MA, Hoffmann GF.
J Cyst Fibros. 2014 Jan;13(1):15-23. doi: 10.1016/j.jcf.2013.06.003. Epub 2013 Jul 25.  

A multi-scale model of hepcidin promoter regulation reveals factors controlling systemic iron homeostasis.
Casanovas G, Banerji A, d'Alessio F, Muckenthaler MU, Legewie S.
PLoS Comput Biol. 2014 Jan;10(1):e1003421. doi: 10.1371/journal.pcbi.1003421. Epub 2014 Jan 2.

The activating STAT5B N642H mutation is a common abnormality in pediatric T-cell acute lymphoblastic leukemia and confers a higher risk of relapse.
Bandapalli OR, Schuessele S, Kunz JB, Rausch T, Stütz AM, Tal N, Geron I, Gershman N, Izraeli S, Eilers J, Vaezipour N, Kirschner-Schwabe R, Hof J, von Stackelberg A, Schrappe M, Stanulla M, Zimmermann M, Koehler R, Avigad S, Handgretinger R, Frismantas V, Bourquin JP, Bornhauser B, Korbel JO, Muckenthaler MU, Kulozik AE.
Haematologica. 2014 Jun 27. pii: haematol.2014.104992. [Epub ahead of print]

High CD45 surface expression determines relapse risk in children with precursor B-cell and T-cell acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol.
Cario G1, Rhein P, Mitlöhner R, Zimmermann M, Bandapalli OR, Romey R, Moericke A, Ludwig WD, Ratei R, Muckenthaler MU, Kulozik AE, Schrappe M, Stanulla M, Karawajew L.
Haematologica. 2014 Jan;99(1):103-10. doi: 10.3324/haematol.2013.090225. Epub 2013 Aug 2.

Pathologies at the nexus of blood coagulation and inflammation: thrombin in hemostasis, cancer and beyond.
Danckwardt, S., M.W. Hentze and A.E. Kulozik. 
J Mol Med (Berl). 2013 Nov;91(11):1257-71. doi: 10.1007/s00109-013-1074-5. Epub 2013 Aug 17.

The RNA-binding protein repertoire of embryonic stem cells.
Kwon, S.C., H. Yi, K. Eichelbaum, S. Föhr, B. Fischer, K.T. You, A. Castello, J. Krijgsveld, M.W. Hentze and V.N. Kim. 
Nature Struc. Mol Biol. 2013 Sep;20(9):1122-30. doi: 10.1038/nsmb.2638. Epub 2013 Aug 4.

Computerized image analysis of iron-stained macrophages.
Benesova K, Schaefer SM, Mall MA, Muckenthaler MU
Ann Hematol 2013 Sep;92(9):1195-9. doi: 10.1007/s00277-013-1740-2. Epub 2013 Apr 17

Mycn and hdac2 cooperate to repress mir-183 signaling in neuroblastoma
Lodrini M, Oehme I, Schroeder C, Milde T, Schier MC, Kopp-Schneider A, Schulte JH, Fischer M, De Preter K, Pattyn F, Castoldi M, Muckenthaler MU, Kulozik AE, Westermann F, Witt O, Deubzer HE
Nucleic Acids Res 2013 Jul; 41:6018-6033

Notch1 activation clinically antagonizes the unfavorable effect of pten inactivation in bfm-treated children with precursor t-cell acute lymphoblastic leukemia.
Bandapalli OR, Zimmermann M, Kox C, Stanulla M, Schrappe M, Ludwig WD, Koehler R, Muckenthaler MU, Kulozik AE
Haematologica 2013 Jun;98:928-936

Iron refractory iron deficiency anemia.
De Falco L, Sanchez M, Silvestri L, Kannengiesser C, Muckenthaler MU, Iolascon A, Gouya L, Camaschella C, Beaumont C
Haematologica 2013 Jun;98:845-853

Nitric oxide-mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in salmonella infection.
Nairz M, Schleicher U, Schroll A, Sonnweber T, Theurl I, Ludwiczek S, Talasz H, Brandacher G, Moser PL, Muckenthaler MU, Fang FC, Bogdan C, Weiss G
J Exp Med. 2013 May 6;210(5):855-73. doi: 10.1084/jem.20121946. Epub 2013 Apr 29

Iron regulatory proteins control a mucosal block to intestinal iron absorption.
Galy, B., D. Ferring-Appel, C. Becker, N. Gretz, H.-J. Gröne, K. Schümann and M.W. Hentze. 
Cell Rep. 2013 Mar 28;3(3):844-57. doi: 10.1016/j.celrep.2013.02.026. Epub 2013 Mar 21.

The murine growth differentiation factor 15 is not essential for systemic iron homeostasis in phlebotomized mice
Casanovas G, Spasic MV, Casu C, Rivella S, Strelau J, Unsicker K, Muckenthaler MU
Haematologica. 2013 Mar;98(3):444-7. doi: 10.3324/haematol.2012.069807. Epub 2012 Sep 14

Novel mutations in the ferritin-l iron-responsive element that only mildly impair irp binding cause hereditary hyperferritinaemia cataract syndrome.
Luscieti S, Tolle G, Aranda J, Campos CB, Risse F, Moran E, Muckenthaler MU, Sanchez M
Orphanet J Rare Dis 2013 Feb 19;8:30

Smad6 and smad7 are co-regulated with hepcidin in mouse models of iron overload.
Vujic Spasic M, Sparla R, Mleczko-Sanecka K, Migas MC, Breitkopf-Heinlein K, Dooley S, Vaulont S, Fleming RE, Muckenthaler MU
Biochim Biophys Acta 2013 Jan;1832:76-84

Pegylated interferon-α induced hypoferremia is associated with the immediate response to treatment in hepatitis C.
Ryan JD, Altamura S, Devitt E, Mullins S, Lawless MW, Muckenthaler MU, Crowe J.
Hepatology. 2012 Aug;56(2):492-500. doi: 10.1002/hep.25666. Epub 2012 Jun 11

Hfe deficiency impairs pulmonary neutrophil recruitment in response to inflammation.
Benesova K, Vujić Spasić M, Schaefer SM, Stolte J, Baehr-Ivacevic T, Waldow K, Zhou Z, Klingmueller U, Benes V, Mall MA, Muckenthaler MU.
PLoS One. 2012;7(6):e39363. Epub 2012 Jun 21

The hemochromatosis proteins HFE, TfR2, and HJV form a membrane-associated protein complex for hepcidin regulation.
D'Alessio F, Hentze MW, Muckenthaler MU.
J Hepatol. 2012 Jun 21.

Regulation of iron homeostasis by microRNAs.
Castoldi M, Muckenthaler MU.
Cell Mol Life Sci. 2012 Jun 9.

Quantitative magnetic analysis reveals ferritin-like iron as the most predominant iron-containing species in the murine Hfe-haemochromatosis.
Gutiérrez L, Vujić Spasić M, Muckenthaler MU, Lázaro FJ.
Biochim Biophys Acta. 2012 Jul;1822(7):1147-53. Epub 2012 Mar 20.

Iron regulatory protein-1 and -2: transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by IRPs.
Sanchez, M., B. Galy, B. Schwanhaeusser, J. Blake, T. Bähr-Ivacevic, V. Benes, M. Selbach, M.U. Muckenthaler and M.W. Hentze.
Blood 118: e168-79, Nov 2011

Opens external link in new windowGrowth differentiation factor 15 in patients with congenital dyserythropoietic anaemia (CDA) type II.
Casanovas G, Swinkels DW, Altamura S, Schwarz K, Laarakkers CM, Gross HJ, Wiesneth M, Heimpel H, Muckenthaler MU.
J Mol Med (Berl). 2011 Aug;89(8):811-6

The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice.
Castoldi M, Vujić Spasić M, Altamura S, Elmén J, Lindow M, Kiss J, Stolte J, Sparla R, D'Alessandro LA, Klingmüller U, Fleming RE, Longerich T, Gröne HJ, Benes V, Kauppinen S, Hentze MW, Muckenthaler MU.
J Clin Invest. 2011 Apr 1;121(4):1386-96

Systems analysis of iron metabolism: the network of iron pools and fluxes.
Lopes TJ, Luganskaja T, Vujić Spasić M, Hentze MW, Muckenthaler MU, Schümann K, Reich JG
BMC Syst Biol. 2010 Aug 13;4:112

Two to tango: regulation of mammalian iron metabolism.
Hentze, M.W., M.U. Muckenthaler, B. Galy and C. Camaschella
Cell 142, 24-38, 2010

The IronChip evaluation package: a package of perl modules for robust analysis of custom microarrays.
Vainshtein, Y., M. Sanchez, A. Brazma, M.W. Hentze, T. Dandekar and M.U. Muckenthaler
BMC Bioinf. 11, 112, 2010

SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression.
Mleczko-Sanecka, K., G. Casanovas, A. Ragab, K. Breitkopf, M. Boutros, S. Dooley, M.W. Hentze and M.U. Muckenthaler.
Blood 115, 2657-2665, 2010.

Bone morphogenetic protein (BMP)-responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJV/BMP/SMAD.
Casanovas G, Mleczko-Sanecka K, Altamura S, Hentze MW, Muckenthaler MU.
J Mol Med. 2009 Feb; 87, 471-480

Hfe acts in hepatocytes to prevent hemochromatosis.
Maja Vujić Spasić, Judit Kiss, Thomas Herrmann, Bruno Galy, Stefanie Martinache, Jens Stolte, Hermann-Josef Gröne, Wolfgang Stremmel, Matthias W. Hentze and Martina U. Muckenthaler.
Cell Metabolism 2008 Feb;7(2):173-8

Ca2+ channel blockers reverse iron overload by a novel mechanism via divalent metal transporter (DMT)-1.
Ludwiczek, S., I. Theurl, M. U. Muckenthaler, M. Jakab, S. Mair, M. Theurl, M. Paulmichl, M.W. Hentze, M. Ritter and G. Weiss.
Nature Medicine 2007 Apr;13(4):448-54

STAT-3 mediates hepatic hepcidin expression and its inflammatory stimulation.
Verga Falzacappa, M.V., Vujic Spasic, M., Hess, R., Stolte, J., Hentze, M.W. and Muckenthaler, M.U.
Blood 2007 Jan 1;109(1):353-8

Physiologic systemic iron metabolism in mice deficient for duodenal Hfe.
Vujic Spasic, M., Kiss, J., Herrmann, T., Hess, R., Stolte, J., Galy, B., Rathkolb, B., Wolf, E., Stremmel, W., Hentze, M.W. and Muckenthaler, M.U.
Blood 2007 May 15;109(10):4511-7. Epub 2007 Jan 30

Previous publications

Research Group's link to University Hospital web page

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