Katarzyna Mleczko-Sanecka, PhD
Laboratory of Iron Homeostasis
International Institute of Molecular and Cell Biology
4 Ks. Trojdena Street, 02-109 Warsaw, Poland
tel: +48 (22) 597 0776; fax: +48 (22) 597 0715
2011 PhD in Biology, European Molecular Biology Laboratory (EMBL) Heidelberg and Heidelberg University, Germany
2007 MSc in Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
2011-2015 Postdoctoral fellow with Martina Muckenthaler and Matthias Hentze, Molecular Medicine Partnership Unit, EMBL Heidelberg and Heidelberg University, Germany
2007-2011 PhD studies with Martina Muckenthaler and Matthias Hentze, Molecular Medicine Partnership Unit, EMBL Heidelberg and Heidelberg University, Germany
2006-2007 Undergraduate research with Jozef Dulak and Alicja Jozkowicz, Department of Medical Biotechnology, Jagiellonian University, Cracow, Poland
2006 Undergraduate research in Claudine Kieda’s laboratory, CNRS, Orleans, France
Achievements and honours:
2015 NCN Polonez Fellowship
2014 Research grant from the University of Heidelberg
2011 Invitation for the 61st Lindau Meeting of Nobel Laureates, Lindau, Germany
2015, 2014, 2011, 2010, 2009 Travel Grants to attend international conferences in iron biology
2007 The PhD Fellowship from the Louis-Jeantet Foundation
2006 ERASMUS Scholarship at the CNRS, Orleans, France
• ^Pasricha SR, Lim PJ, Duarte TL, Casu C, Oosterhuis D, Mleczko-Sanecka K, Suciu M, Da Silva AR, Al-Hourani K, Arezes J, McHugh K, Gooding S, Frost JN, Wray K, Santos A, Porto G, Repapi E, Gray N, Draper SJ, Ashley N, Soilleux E, Olinga P, Muckenthaler MU, Hughes JR, Rivella S, Milne TA, Armitage AE, Drakesmith H. Hepcidin is regulated by promoter-associated histone acetylation and HDAC3. Nat Commun. 2017; 8(1):403
• ^Mleczko-Sanecka K, da Silva AR, Call D, Neves J, Schmeer N, Damm G, Seehofer D, Muckenthaler MU. Imatinib and spironolactone suppress hepcidin expression. Haematologica, 2017; 102(7):1173-84
• Tejchman A, Lamerant-Fayel N, Jacquinet JC, Bielawska-Pohl A, Mleczko-Sanecka K, Grillon C, Chouaib S, Ugorski M, Kieda C. Tumor hypoxia modulates podoplanin/CCL21 interactions in CCR7+ NK cell recruitment and CCR7+ tumor cell mobilization. Oncotarget, 2017; 8(19):31876-87
• Mleczko-Sanecka K, Roche F, da Silva AR, Call D, D’Alessio F, Ragab A, Lapinski PE, Ummanni R, Korf U, Oakes C, Damm G, D’Alessandro LA, Klingmüller U, King PD, Boutros M, Hentze MW, Muckenthaler MU. Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to proliferative Ras/RAF and nutrient-dependent mTOR signaling. Blood, 2014; 123(10):1574-85 (Article with a comment: Arosio P. New signaling pathways for hepcidin regulation. Blood, 2014; 123(10):1433-4)
• Sonnweber T, Nachbaur D, Schroll A, Nairz M, Seifert M, Demetz E, Haschka D, Mitterstiller AM, Kleinsasser A, Burtscher M, Trübsbach S, Murphy AT, Wroblewski V, Witcher DR, Mleczko-Sanecka K, Vecchi C, Muckenthaler MU, Pietrangelo A, Theurl I, Weiss G. Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB. Gut, 2014; 63(12):1951-9
• Vujić Spasić M, Sparla R, Mleczko-Sanecka K, Migas MC, Breitkopf-Heinlein K, Dooley S, Vaulont S, Fleming RE, Muckenthaler MU. Smad6 and Smad7 are co-regulated with hepcidin in mouse models of iron overload. Biochim Biophys Acta, 2013; 1832(1):76-84
• Mleczko-Sanecka K, Casanovas G, Ragab A, Breitkopf K, Müller A, Boutros M, Dooley S, Hentze MW, Muckenthaler MU. SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression. Blood, 2010; 115(13):2657-65
• Casanovas G, Mleczko-Sanecka K, Altamura S, Hentze MW, Muckenthaler MU. Bone morphogenetic protein (BMP)-responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJV/BMP/SMAD. J Mol Med, 2009; 87(5):471-80
• Jozkowicz A, Was H, Taha H, Kotlinowski J, Mleczko K, Cisowski J, Weigel G, Dulak J. 15d-PGJ2 upregulates synthesis of IL-8 in endothelial cells through induction of oxidative stress. Antioxid Redox Signal, 2008; 10(12):2035-46
• Funovics P, Brostjan C, Nigisch A, Fila A, Grochot A, Mleczko K, Was H, Weigel G, Dulak J, Jozkowicz A. Effects of 15d-PGJ(2) on VEGF-induced angiogenic activities and expression of VEGF receptors in endothelial cells. Prostaglandins Other Lipid Mediat, 2006; 79(3-4):230-244
^Publications with IIMCB affiliation
POLONEZ (NCN), 2015/19/P/NZ2/03278, Deciphering BMP6 regulatory mechanisms using CRISPR/Cas9-based screening approach
Sufficient iron supplies are critical for vital cellular functions, such as energy production and RNA/DNA processing and repair. In the human body, the vast majority of iron is utilized for hemoglobin synthesis during the daily production of ~200 billion erythrocytes.1,2 However, excess of free iron causes oxidative damage, leading to organ failure. Maintenance of an appropriate iron balance is therefore essential for the correct functioning of cells and organisms, and an increasing understanding of the genetic control of iron homeostasis is important for human health. In mammals, appropriate body iron balance is chiefly ensured by the hepcidin-ferroportin axis (Fig. 1A).1,2 Hepcidin is a small hormone that is produced by liver hepatocytes. It binds to the iron exporter ferroportin to trigger its degradation and inhibit iron release from specialized iron-exporting cells, mainly in the duodenum and the spleen. Iron export via ferroportin determines iron saturation of the plasma protein transferrin, and hence controls availability of iron in the body. Despite growing knowledge of the molecular control of iron homeostasis, the genetic basis for the variation in body iron parameters in health and disease is still not fully explained.3 Thus, it is expected that still elusive mechanisms modify such processes as iron sensing, iron fluxes, or iron deposition. The major objective of research in the Laboratory of Iron Homeostasis is to better understand the mechanism that affect iron sensing and iron accumulation in health and disease. To this end we are combining approaches of functional genomics (eg, CRISPR genetic screens) with different cell-based assays and mouse-based studies.
When iron levels in the body increase, hepcidin production is enhanced to prevent further iron absorption from the diet. To gain insights into the genetic control of iron homeostasis, we previously designed and conducted large-scale RNAi screens for novel hepcidin regulators (Mleczko-Sanecka et al., 2010, 2014). This work identified SMAD7 as an important hepcidin inhibitor and linked hepcidin control to proliferative signaling. Furthermore, our screens generated comprehensive lists of potential modifiers of iron homeostasis. Based on the screening data, we have also sought to identify and develop hepcidin-modifying drugs. Our recently published results demonstrate that a commonly used antihypertensive drug, spironolactone, which is prescribed for the treatment of heart failure, acne, and female hirsutism, and imatinib, a first-line, lifelong therapeutic option for some frequent cancer types, suppress hepcidin expression in cultured cells and in mice (Mleczko-Sanecka et al., 2017). We expect these findings to be relevant to patient management, which needs to be addressed in prospective clinical studies.
Bone morphogenetic protein (BMP) signaling is a key pathway for iron-dependent hepcidin regulation.4 BMP6 emerged as a critical endogenous BMP iron sensor. Bmp6 is oppositely regulated by low and high body iron levels,5 which occurs specifically in the liver.6 Further studies demonstrated that both systemic and endothelial-specific Bmp6 knock-out mice show hepcidin deficiency and develop iron overload disease,7,8 identifying liver sinusoidal endothelial cells (LSECs) as the critical producers of liver BMP6. Despite this knowledge, it remains not clear how systemic iron-triggered signals translate into increased Bmp6 mRNA levels in LSECs. One objective of our work is thus to dissect iron-dependent regulatory mechanisms that induce endothelial BMP6 production (Fig. 1B).
If iron challenge persists, or when hepcidin responses are dysregulated (eg, as in a frequent genetic disease hereditary hemochromatosis)9 iron overload progresses. Tissue iron deposition is largely mediated by non-transferrin bound iron (NTBI) species which are generated in the circulation when iron saturation of transferrin exceeds its iron-binding capacity.10 This form of ‘free iron’ is highly toxic and is currently considered a main contributor to the pathology of iron-overload disorders. Another line of our research seeks to better understand the molecular processes that contribute to NTBI iron uptake in hepatocytes, the major cell type that accumulates iron in iron overload-related diseases (Fig. 1B).10,11
Fig. 1. (A) Systemic iron homeostasis is maintained by the hepcidin/ferroportin axis. (B) Under iron-rich conditions production of hepcidin is stimulated in hepatocytes by BMP6, an angiokine released from liver sinusoidal endothelial cells (LSECs). One aim of our research is to dissect mechanisms that control iron-triggered induction of BMP6, and thereby to better understand the process of iron-sensing in the liver. Another major objective of work in our laboratory is to better characterize molecular mechanisms that are responsible for accumulation of non-transferrin bound iron (NTBI) in the liver.
1. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell. 2010;142(1):24-38.
2. Muckenthaler MU, Rivella S, Hentze MW, Galy B. A Red Carpet for Iron Metabolism. Cell. 2017;168(3):344-361.
3. Pichler I, Minelli C, Sanna S, et al. Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels. Human molecular genetics. 2011;20(6):1232-1240.
4. Babitt JL, Huang FW, Wrighting DM, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38(5):531-539.
5. Kautz L, Meynard D, Monnier A, et al. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood. 2008;112(4):1503-1509.
6. Kautz L, Besson-Fournier C, Meynard D, Latour C, Roth MP, Coppin H. Iron overload induces BMP6 expression in the liver but not in the duodenum. Haematologica. 2011;96(2):199-203.
7. Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth MP. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet. 2009;41(4):478-481.
8. Canali S, Zumbrennen-Bullough KB, Core AB, et al. Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice. Blood. 2017;129(4):405-414.
9. Pietrangelo A. Iron and the liver. Liver Int. 2016;36 Suppl 1:116-123.
10. Brissot P, Ropert M, Le Lan C, Loreal O. Non-transferrin bound iron: a key role in iron overload and iron toxicity. Biochim Biophys Acta. 2012;1820(3):403-410.
11. Jenkitkasemwong S, Wang CY, Coffey R, et al. SLC39A14 Is Required for the Development of Hepatocellular Iron Overload in Murine Models of Hereditary Hemochromatosis. Cell Metab. 2015;22(1):138-150.
Katarzyna Mleczko-Sanecka, PhD
MSc Piotr Kabelis, MSc
Aleksandra Szybińska, MSc