Regulation of systemic iron homeostasis by microRNA-122
Final Report Abstract
Our data show for the first time that (i) liver specific miR‐122 is required to maintain systemic iron homeostasis; (ii) miR‐122 directly regulates expression of Hfe and hemojuvelin; (iii) miR‐122 induced iron deficiency results in the activation of extramedullary erythropoiesis; (iv) up‐stream regulators of hepcidin expression are also required to maintain miR‐122 transcription; and that (v) the cytokines Tgf‐β and Bmp‐6 differentially regulate miR‐122 transcription in a SMAD4‐dependent manner. Future experiments will have to identify the element in the miR‐122 promoter responsive to Tgf‐β and BMP‐ 6 regulation and to identify the physiological role played by this mechanism. Based on our findings, we propose the following model for the role of miR‐122 in iron homeostasis: miR‐122 regulates the expression of the HH‐associated proteins Hfe, hemojuvelin and possibly others. Over‐expression of Hfe and hemojuvelin activates hepcidin mRNA expression. Elevated hepcidin levels will limit the iron export capacity from duodenal enterocytes and macrophages and cause plasma and liver iron deficiency. As a consequence, iron‐deficient hematopoiesis develops and extramedullary hematopoiesis is observed in the spleen. In the proposed model miR‐122 functions to fine‐tune hepcidin expression in response to changes in body iron demands. Equally important, the model infers that Hfe and hemojuvelin are critical upstream regulators of miR‐122 levels, likely as a consequence of the signaling activities impaired by the lack of Hfe or Hemojuvelin. It is known that Hfe deficiency attenuates the BMP/Smad signaling pathway in Hereditary Hemochromatosis patients and the respective murine disease model, while molecular pathways downstream to the BMP co‐receptor hemojuvelin activates smad‐dependent hepcidin transcription.
Publications
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“Expression of spinal cord microRNAs in a rat model of chronic neuropathic pain” Neurosci Lett. 2011 Nov 23 [Epub ahead of print]
Brandenburger T, Castoldi M, Brendel M, Grievink H, Schlösser L, Werdehausen R, Bauer I, Hermanns H
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“Expression profiling of circulating miRNAs as a novel non‐invasive diagnostic tool” European Pharmaceutical Review Issue 6, 13 December (2011)
Castoldi M
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“The liver‐specific microRNA‐122 controls systemic iron homeostasis in the mouse” J Clin Invest. Mar 1, (2011)
Mirco Castoldi, Maja Vujić Spasić, Sandro Altamura, Joacim Elmén, Morten Lindow, Judit Kiss, Jens Stolte, Richard Sparla, Lorenza A D’Alessandro, Ursula Klingmueller, Robert E Fleming, Thomas Longerich, Hermann J Gröne, Vladimir Benes, Sakari Kauppinen, Matthias W Hentze, and Martina U Muckenthaler
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“Regulation of iron homeostasis by microRNAs” Cell Mol Life Sci. 2012 Jun 9 [Epub ahead of print]
Castoldi M and Martina U Muckenthaler
