Molecular Medicine Partnership UnitResearch Groups
Iron homeostasis in health and disease
Matthias W. 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:
- molecular mechanisms underlying hereditary hemochromatosis;
- signalling pathways underlying hepcidin regulation and
- 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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Research Focus 4: MicroRNAs in iron metabolism
Identification of the role of microRNAs in iron metabolism
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Selected publications
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
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
Growth 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