Professional path:
Martina Muckenthaler is a Professor of Molecular Medicine at the Department of Pediatric Hematology, Oncology and Immunology at the Ruprecht-Karls-University in Heidelberg as well as group leader within the Molecular Medicine Partnership Unit (MMPU) between the University of Heidelberg and the European Molecular Biology Laboratory (EMBL).
She was trained as a molecular biologist in leading international research laboratories in Munich, London and at the University of Oxford (UK) for her PhD, before she joined the EMBL for her postdoctoral work.
Research focus and publication record:
Martina Muckenthaler’s longstanding research interest focuses on human iron metabolism and the molecular pathophysiology of genetic and acquired iron overload and iron deficiency diseases.
She was the primary author of two publications in Nature Genetics that laid foundations for the understanding of hereditary hemochromatosis as a hepcidin deficiency disease (2003 and 2004). She further demonstrated that the key molecular defect for hereditary hemochromatosis localizes to hepatocytes (Cell Metabolism, 2008). The Muckenthaler team gained detailed insights into the regulatory mechanisms that control the expression of the iron hormone hepcidin and its receptor ferroportin (all published in prestigious, high impact journals including Cell Metabolism, Journal of Clinical Investigation and BLOOD). Important current work focuses on the pathophysiological consequences of iron overload and iron deficiency (e.g. Cell Metabolism 2014, Blood 2016 and 2018, Nature Communications 2018, and the European Heart Journal 2019).
Honours and Awards
Her scientific achievements have been recognized in multiple ways, including the Margrit Krikker Award for Young Investigators of the International BioIron Society (2007), her election as Director of the International BioIron Society (2009-2013), the Reeves Prize for her hypoxia research (2015), and most recently, the election to the Presidency of the International BioIron Society (2019-2021). She actively serves influential academic societies and committees, e.g. as the Chair of the Scientific Committee of the American Society of Hematology (ASH), the chair of the European fellowship and grant program of the EHA, as a member of the Executive Board of the European Hematology Association (EHA) as well as a Board Member of the ‘German Society for Biochemistry and Molecular Biology.’ As Chair of the Scientific Program Committee of the EHA she was responsible for the program of EHA ‘23 in Stockholm, a congress that attracted more than 13000 participants. Since 2020 she is an elected member of the German Academie of Science/Leopoldina.
- Regulatory mechanisms controlling iron homeostasis
- Diseases with imbalanced iron homeostasis
- Lung diseases
- Lung Cancer
- Pulmonary Hypertension
- Acute Lung Injury
- Marques O, Horvat NK, Zechner L, Colucci S, Sparla R, Zimmermann S, Neufeldt CJ, Altamura S, Qiu R, Müdder K, Weiss G, Hentze MW, Muckenthaler MU. Inflammation-driven NFκB signaling represses Ferroportin transcription in macrophages via HDAC 1 and 3. Blood. 2024 Dec 10:blood.2023023417. doi: 10.1182/blood.2023023417. PMID: 39656097.
- Horvat NK, Chocarro S, Marques O, Bauer TA, Qiu R, Diaz-Jimenez A, Helm B, Chen Y, Sawall S, Sparla R, Su L, Klingmüller U, Barz M, Hentze MW, Sotillo R, Muckenthaler MU Superparamagnetic Iron Oxide Nanoparticles Reprogram the Tumor Microenvironment and Reduce Lung Cancer Regrowth after Crizotinib Treatment. ACS Nano. 2024 Apr 30;18(17):11025-11041. doi: 10.1021/acsnano.3c08335. Epub 2024 Apr 16. PMID: 38626916
- Galy B, Conrad M, Muckenthaler M. Mechanisms controlling cellular and systemic iron homeostasis. Nat Rev Mol Cell Biol. 2024 Feb;25(2):133-155. doi: 10.1038/s41580-023-00648-1. Epub 2023 Oct 2. Erratum in: Nat Rev Mol Cell Biol. 2024 Aug;25(8):671. doi: 10.1038/s41580-024-00760-w. PMID: 37783783.
- Ruban Agarvas A, Kopf S, Lopes TJS, Atkins JL, Thalmann P, Fernández-Real JM, Nawroth P, Muckenthaler MU. Iron biomarkers predict peripheral artery disease in females. Atherosclerosis. 2025 Mar;402:119111. doi: 10.1016/j.atherosclerosis.2025.119111. Epub 2025 Jan 28. PMID: 39923542.
- Marques O, Muckenthaler MU. Alterations of iron homeostasis as a potential druggable driver of long COVID. Nat Immunol. 2024 Mar;25(3):387-389. doi: 10.1038/s41590-024-01759-3. PMID: 38429459.
- Bauer TA, Horvat NK, Marques O, Chocarro S, Mertens C, Colucci S, Schmitt S, Carrella LM, Morsbach S, Koynov K, Fenaroli F, Blümler P, Jung M, Sotillo R, Hentze MW, Muckenthaler MU, Barz M. Core Cross-Linked Polymeric Micelles for Specific Iron Delivery: Inducing Sterile Inflammation in Macrophages. Adv Healthc Mater. 2021 Oct;10(19):e2100385. doi: 10.1002/adhm.202100385. Epub 2021 Jun 16.
Dr. Sandro Altamura | Postdoc |
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Colucci, Silvia | PhD Student |
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Horvat, Natalie | PhD Student |
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Dr. Marques, Oriana | Postdoc |
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Dr. Mertens, Christina | Postdoc |
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Qiu, Ruiyue | PhD Student |
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Ruban Agarvas, Anand | PhD Student |
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Zechner, Laura | PhD Student |
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Lung Research - Projects
- Iron-loaded tumor-associated macrophages (iTAMs) show a pro-inflammatory phenotype, hallmarked by anti-tumorigenic activity and an ability to attenuate tumor growth. The team explored the relevance of these findings in lung cancer patients by investigating the impact of the iTAM content in the tumor microenvironment (TME) on patient survival. They analyzed human non-small cell lung cancer (NSCLC) paraffin-embedded archival tissue samples for iron levels and macrophage numbers. Interestingly, patients with lung adenocarcinoma accumulating iron in the TME show higher numbers of M1-like pro-inflammatory TAMs and a survival advantage compared to iron-negative patients. By contrast, in patients with lung squamous cell carcinoma iron in the TME does not affect survival, suggesting a unique influence of iron on different histological subtypes of non-small cell lung cancer (NSCLC). They conclude that in lung adenocarcinoma iron may serve as a prognostic marker for patient survival and as a potential therapeutic target for anti-cancer therapy.
- Tumor-associated macrophages (TAMs) frequently help to sustain tumor growth and mediate immune suppression in the tumor microenvironment (TME). The team identified a subset of iron-loaded, pro-inflammatory TAMs localized in hemorrhagic areas of the TME. The occurrence of iron-loaded TAMs (iTAMs) correlated with reduced tumor size in patients with non-small cell lung cancer. Ex vivo experiments established that TAMs exposed to hemolytic red blood cells (RBCs) were converted into pro-inflammatory macrophages capable of directly killing tumor cells. This anti-tumor effect could also be elicited via iron oxide nanoparticles. When tested in vivo, tumors injected with such iron oxide nanoparticles led to significantly smaller tumor sizes compared to controls. These results identify hemolytic RBCs and iron as novel players in the TME that repolarize TAMs to exert direct anti-tumor effector function. Thus, the delivery of iron to TAMs emerges as a simple adjuvant therapeutic strategy to promote anti-cancer immune responses.
- Emerging evidence suggests that pulmonary iron accumulation is implicated in a spectrum of chronic lung diseases. However, the mechanism(s) involved in pulmonary iron deposition and its role in the in vivo pathogenesis of lung diseases remains unknownThe team showed that a point mutation in the murine ferroportin gene, which causes hereditary hemochromatosis type 4 (Slc40a1C326S), increases iron levels in alveolar macrophages, epithelial cells lining the conducting airways and lung parenchyma, and in vascular smooth muscle cells. Pulmonary iron overload is associated with oxidative stress, restrictive lung disease with decreased total lung capacity and reduced blood oxygen saturation in homozygous Slc40a1C326S/C326S mice compared to wild-type controls. These findings implicate iron in lung pathology, which is so far not considered a classical iron-related disorder.
- Iron accumulates in the lungs of patients with common respiratory diseases or transfusion-dependent beta-thalassemia. Based on previous work, the team hypothesized that systemic iron overload affects the alveolar region of the lung and in particular the surfactant producing alveolar epithelial type II (AE2) cells. The team showed that disruption of systemic iron homeostasis and iron overload affects the ultrastructure of interalveolar septa which is characterized by membrane-bound iron storage in AE1 cells, thickening of the air-blood barrier and hyperplasia and hypotrophy of AE2 cells despite normal total intracellular surfactant pools.
- Ferroportin (FPN) exports iron from duodenal enterocytes, macrophages, and hepatocytes to maintain systemic iron homeostasis. In addition, FPN is expressed in various cancer cells. The team showed that in lung cancer, FPN expression is regulated by miR-20a. Within the FPN-3'-untranslated region (3'UTR), we identify and experimentally validate three evolutionarily conserved target sites for the microRNA (miRNA) members of the miR-17 seed family, including miR-20a. The team’s analysis of RNA sequencing data from patients with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) revealed that FPN messenger RNA (mRNA) levels are significantly decreased in tumor compared to matched healthy tissue, while miR-20a levels are increased. A significant negative correlation of miR-20a and FPN expression was observed. Functional studies further demonstrate that FPN is post-transcriptionally regulated by miR-20a in non-small cell lung cancer (NSCLC) cells and that overexpression or knockdown of miR-20a or FPN affects NSCLC proliferation and colony formation. Taken together, their data suggest that increased expression of miR-20 in lung cancer may decrease iron export, leading to intracellular iron retention, which, in turn, favors cell proliferation.
