Heme (iron protoporphyrin IX) serves as the functional group of various proteins, including hemoglobin, myoglobin, nitricoxide synthase, and cytochromes, and is therefore essentialfor diverse biologic processes. On the other hand, heme that is not bound to proteins is a potential toxic molecule as it can promote the generation of reactive oxygen species, causing cellular damage. Thus, heme homeostasis is tightly controlled at the level of synthesis, degradation and absorption from the diet.
The work of this Research Group is aimed at the identification and functional characterization of genes involved in heme metabolism, particularly in heme trafficking between different organs. Moreover, the Unit is interested in the role of these genes in the pathogenesis of iron related disorders.
Historically, this Research Group has worked on the functional characterization of heme and hemoprotein plasma transporters, i.e. hemopexin and haptoglobin, under physiologic and pathologic conditions. More recently, it has focused its attention on the heme exporter Feline Leukaemia Virus subgroup C Receptor (FLVCR).
The main lines of research are the following:
Mechanisms of heme detoxification by the liver. The liver is the main organ responsible for detoxification of excess heme, and Hemopexin mediates heme transport from sites of heme production to the liver. Once in hepatocytes, heme is thought to be degraded by heme oxygenase. However, recently reported experimental evidence suggests that heme export from hepatocytes to bile canaliculi plays a crucial role in removing excess heme from the organism. We have already reported that lack of hemopexin causes endothelial activation and organ inflammation.
This project is aimed at the characterization of the role of FLVCR and hemopexin in heme detoxification under pathologic conditions associated to intravascular hemolysis.
Mechanisms of heme absorption by the duodenum. Most work in the field of iron metabolism in the last decades has been focused on the characterization of inorganic iron absorption. This work led to the identification of molecules involved in iron import from intestinal lumens to enterocytes, in iron export from enterocytes to plasma, and in iron delivery to tissues. On the other hand, even if the bioavailability of heme is higher than that of inorganic iron, little is known about the mechanisms controlling heme absorption. This project is aimed at the characterization of the role of FLVCR and hemopexin in heme export from enterocytes, and its delivery to other tissues.
Mechanisms of control of heme level in the central nervous system (CNS). CNS is separated from the body by the blood-brain barrier and has therefore evolved mechanisms of local heme and iron management. FLVCR, haptoglobin and hemopexin are expressed in the CNS, the latter with a well-established role in the control of cerebral iron levels.
We have recently demonstrated that hemopexin modulates oligodendrocyte differentiation and the myelination state of brain. We are interested in defining the mechanisms of these processes and the role of hemopexin in pathologic conditions characterized by demyelination, i.e. multiple sclerosis.
The role of heme in the control of erythropoiesis and in embryo development. It has already been reported that FLVCR is essential for erythropoiesis and proper skeletal formation during development. We have recently identified a novel FLVCR isoform and produced a murine Flvcr mutant allele that is lethal at mid-gestation, with phenotypic abnormalities resembling those observed in human patients suffering from Diamond-Blackfan anemia. The characterization of this model is currently under investigation.
HeLa cells overexpressing different FLVCR isoforms
Defects in iron metabolism are the basis of several pathologic conditions, including anemia, inflammation and neurodegenerative diseases. This group is interested in the pathogenesis of Diamond-Blackfan anemia, for which FLVCR is a good candidate; in heme-mediated tissue inflammation and in demyelination disorders. |
Tolosano E, Fagoonee S, Garuti C, Valli L, Andrews NC, Altruda F, Pietrangelo A., “Haptoglobin modifies the hemochromatosis phenotype in mice”, Blood 105 (8): 3353-5 (2005)
Fagoonee S., Gburek J., Hirsch E., Marro S., Moestrup S.K., Laurberg J.M., Christensen E.I., Silengo L., Altruda F. and Tolosano E., “Plasma protein Haptoglobin modulates renal iron loading”, Am J Pathol 166(4): 973-83 (2005)
Ascenzi P., Bocedi A., Visca P., Altruda F., Tolosano E., Beringhelli T. and Fasano M., “Hemoglobin and Heme Scavenging”, IUBMB Life 57 (11): 749-759 (2005)
Fagoonee S., Di Cunto F., Vozzi D., Volinia S., Pellegrino M., Gasparini P., Silengo L., Altruda F. and Tolosano E., “Microarray and large-scale in silico-based identification of functional modules involving Haptoglobin and/or Hemopexin”, DNA and Cell Biology, 25 (6), 323-330 (2006)
Marro S., Barisani D., Chiabrando D., Fagoonee S., Muckenthaler M., Stolte J., Meneveri R., Haile D., Silengo L., Altruda F. and Tolosano E., “Lack of Haptoglobin affects iron transport across duodenum by modulating Ferroportin expression”, Gastroenterology, 133(4):1261-1271 (2007)
Vinchi F., Gastaldi S., Silengo L., Altruda F. and Tolosano E., “Hemopexin prevents endothelial damage and liver congestion in a mouse model of heme overload”, Am J Pathol 173(1): 289-299 (2008)
Fagoonee S., Caorsi C., Giovarelli M., Stoltenberg M., Silengo L., Altruda F., Camussi G. Tolosano E. and Bussolati B, “Lack of plasma protein hemopexin dampens mercury-induced autoimmune response in mice”, J. Immunol 181: 1937-1947 (2008)
Morello N., Tonoli E., Logrand F., Fiorito V., Fagoonee S., Turco E., Silengo L., Vercelli A., Altruda F. and Tolosano E., “Hemopexin affects iron distribution and ferritin expression in mouse brain”, J. Cell Mol Med, 13, 4192-204 (2009). Epub DOI: 10.1111/j.1582-4934.2008.00611.x (2008)
Li RC, Saleem S, Zhen G, Cao W, Zhuang H, Lee J, Smith A, Altruda F, Tolosano E, Doré S., Heme-hemopexin complex attenuates neuronal cell death and stroke damage. J Cereb Blood Flow Metab 29(5):953-64 (2009)
Tolosano E, Fagoonee S, Morello N, Vinchi F, Fiorito V., Heme Scavenging and the other facets of Hemopexin. Antioxidants & Redox Signaling, 12(2): 305-20 (2010)
Marro S., Chiabrando D., Messana E., Stolte J., Hentze M.W., Turco E., Tolosano E. and Muckenthaler M.U., “Hemoglobin controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position -7007 of the FPN1 promoter”, Haematologica, Epub DOI:10.3324/haematol.2009.020123 (2010) |
