The role of iron in health and disease

Introduction to the interests of the lab

Lab members
- Martina U. Muckenthaler
- Maja Vujić Spasić (Postdoc)
- Flavia d’Allesio (PhD student)
- Guillem Casanovas (PhD student)
- Kasia Mleczko-Sanecka (PhD student)
- Mayka Sanchez (Postdoctoral fellow)
- Sandro Altamura (Postdoctoral fellow)
- Wolfgang Gilles (Postdoctoral fellow)
- Mingang Zhu (Postdoctoral fellow)
- Mirco Castoldi (Postdoctoral fellow)
- Richard Sparla (Technical assistant)

Lab publications

Introduction to the interests of the lab

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 regulation of genes involved in iron metabolism and its disturbances in human disease.

One major research focus of the lab is to understand molecular mechanisms involved in hereditary hemochromatosis (HH), the most prevalent genetic disorder in the western world. The disease is mainly caused by mutations in the HFE gene, which codes for a MHC class I like molecule. Work from our lab and others demonstrated that HFE is required for appropriate hepatic expression of the iron hormone and anti-microbial peptide hepcidin: expression of this negative regulator of duodenal iron absorption is decreased and cannot be adjusted in response to elevated hepatic iron levels in Hfe-deficient mice and HH patients. These findings further our understanding of the molecular mechanism of Hfe function and suggest that the primary locus of Hfe function is the liver and not the duodenum, as was previously hypothesized. Indeed, analysis of tissue specific Hfe knock-out mice has recently unambiguously demonstrated that local Hfe expression in hepatocytes serves to maintain physiological iron homeostasis, answering this longstanding question in medicine. Additionally, HFE controls hepcidin expression in response to inflammatory stimuli. This links HFE to the immune system and to the anemia of chronic diseases (ACD), which results in iron redistribution in response to inflammation, infection and malignancy.

An important challenge is now to understand how signalling pathways in general and the hemochromatosis-associated proteins, specifically, regulate hepcidin expression. To identify cis-acting elements and trans-acting factors for hepcidin expression under steady state conditions and in response to experimental (e.g. inflammatory) stimuli, we established a cell-based assay system and luciferase reporter vectors containing the human hepcidin promoter. Applying these tools we were able to show that a STAT-binding motif at position -64/-72 of the hepcidin promoter and STAT-3 are critical determinants for the control of hepcidin mRNA expression both under inflammatory and steady state conditions. In addition we uncovered a distinct BMP-responsive element (BMP-RE) located immediately adjacent to the STAT-3 binding site at position -84/-79bp. The BMP-RE is multi-functional because it controls HFE2-mediated hepcidin promoter activity as well as its inflammatory response to IL-6. These data uncover a point of cross-talk for hepcidin regulation by hemojuvelin and inflammatory stimuli.

Part of our 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.
Specifically, we plan to investigate three themes: (1) the hepcidin/ferroportin regulatory system and its involvement in hemochromatosis, the thalassemias and the anemias of chronic disease (2) the IRE/IRP regulatory system and its possible involvement in disease (3) a potential role of microRNAs in iron metabolism.