Metabolismo del

ferro:ulteriori
acquisizioni e nuove
entità nosografiche.
Auditorium Ordine dei Medici
Benevento
20 Dicembre 2008
D. Parente
Ospedale Sacro Cuore di Gesù
Dipartimento dei Servizi Diagnostici
Fatebenefratelli
Benevento
Importanza biologica del ferro

 Emoglobina
 Mioglobina
 Enzimi coinvolti nelle attività
metaboliche cellulari:
 Ossidoriduzione
 Catena respiratoria
 Sintesi del DNA
 Proliferazione cellulare
 Risposta all’infiammazione
 Sintesi di ormoni e neurotrasmettitori
 Tossicità del ferro

Radicali liberi

Meccanismo perossidativo:

Mitocondri
Lisosomi
membrana plasmatica
Morte
Proteine cellulare
DNA
 Ferro corporeo
totale e suoi compartimenti

Ferro funzionale:
emoglobina,
mioglobina, enzimi
emici e
flavoproteine.
Ferro di deposito:
ferritina,emosiderina
Ferro di trasporto:
nel plasma legato
alla transferrina

Aisen P., Wessling-Resnick M., Leibold E.A.. Iron

Metabolism. Curr.Opin. Chem. Biol. 1999; 3:200-6.
 Ferro corporeo
totale e suoi compartimenti

 Ferro funzionale:
emoglobina,
mioglobina, enzimi
emici e flavoproteine.
 Ferro di deposito:
ferritina,emosiderina
 Ferro di
trasporto: nel
plasma legato alla
transferrina

Pietrangelo A. N Engl J Med 2004;350:2383-2397

Dieta e ferro
Dieta e ferro
Villo intestinale
ed enterocita

L’epitelio intestinale è organizzato in villi rivestiti da

epitelio monostratificato
le cui singole cellule sono deputate all’assorbimento
 Punti chiave del
metabolismo del ferro
 Enterocita

Dorine et al.Clinical
Chemistry 2006

 Iron in food can be present in an inorganic form (Fe3+) or as hemoglobin or

myoglobin. Fe3+ in soluble iron complexes is reduced to Fe2+ by DcytB in
the brush border and is transported into the duodenal enterocytes by DMT1.
Heme enters the enterocyte after enzymatic digestion of hemoglobin and
myoglobin, presumably through a heme cell transport protein, HCP1 (166).
Within the enterocyte, heme is degraded by heme oxygenase ( HO), and
Fe2+ iron is released. From there, iron is either stored as ferritin or
transported across the basolateral membrane to enter the circulation. This
transport across the basolateral membrane is mediated by the iron
transporter ferroportin, which transports Fe2+ to the plasma, where it is
oxidized to Fe3+ by hephaestin, a membrane-resident multicopper oxidase
very similar to ceruloplasmin ( Cp), facilitating binding to transferrin ( Tf).
 Precursori
eritroidi

Erythroid precursors take up iron through the transferrin cycle. Transferrin

binds to TfR1 on the cell surface. The complexes localize to clathrin-coated
pits, which invaginate to initiate endocytosis. In specialized endosomes, a
decrease in pH induces the release of iron from transferrin. Fe3+ is
converted to Fe2+, presumably by STEAP3 (168), which enables iron
transport out of the endosomes via DMT1. Subsequently, apotransferrin
(apo-Tf) and the TfR1 both return to the cell surface. Both proteins participate
in further rounds of iron delivery. Iron is transported mainly into mitochondria
for incorporation into heme and Fe-S proteins. Excess iron is stored as
ferritin and hemosiderin. In erythroid cells, essentially all iron is incorporated
into hemoglobin
Dorine et al.Clinical Chemistry 2006
 Macrofagi

 Reticuloendothelial macrophages carry out iron

recycling. They ingest senescent erythrocytes and
lyse them in a phagolysosomal compartment.
Hemoglobin (Hb) is degraded, and iron is liberated
from heme. The enzyme heme oxygenase (HO)
participates in this process. Iron is then either
stored as ferritin or exported out of the cell by
ferroportin and ceruloplasmin (Cp). A considerable
amount of iron is released as ferritin or hemoglobin
(201).

Dorine et al.Clinical Chemistry 2006

 Epatociti

 Hepatocytes take up iron through multiple pathways. The

molecules involved in transport of NTBI, hemoglobin
(Hb), heme (Haem), and ferritin have not yet been
identified. As in macrophages, iron in hepatocytes is
either stored as ferritin and hemosiderin or exported out
of the cell by ferroportin and subsequently oxidized by
ceruloplasmin (Cp) before binding to transferrin (Tf).
Available data do suggest that HFE in interaction with
TfR1 and parallel to TfR2 is implicated in the iron-sensing
pathway of hepatocytes that controls hepcidin synthesis

Dorine et al.Clinical Chemistry 2006

Phillip S.Oates
2007
Phillip
S.Oates2007
Phillip
S.Oates2007
Epcidina
Come è avvenuta la sua identificazione?
Hep cidin
Identificata nel 2000
Park e collaboratori mentre
caratterizzavano le proprietà
antimicrobiche di alcuni fluidi
organici,hanno isolato un nuovo
peptide dalle urine umane.
Hepatic

Bacteriocidal
protein

Park CH, Valore EV, Waring AJ, Ganz T.

Hepcidin, a urinary antimicrobial peptide
synthesized in the liver. J Biol Chem.
2001;276:7806-7810.
 Epcidina
Come la si è contestualizzata nel metabolismo del ferro?

I topi USF2 knock-out

sviluppavano una emocromatosi
spontanea con progressiva
deposizione del ferro nel fegato,
nel pancreas e nella milza ed i loro
fegati mancavano di mRNA per
l’epcidina
Nicolas G, Bennoun M, Devaux I, et al. Lack
of hepcidin gene expression and severe
tissue iron overload in upstream stimulatory
factor 2 (USF2) knockout mice. Proc Natl
Acad Sci U S A. 2001; 98:8780-8785.
Processamento dell’Epcidina
Codificata dal gene HAMP (19q13)

Sequenza aminoacidica

Forme predominanti nel plasma e nelle urine:

•hep-20
•hep-25
 Epcidina
Come è strutturata?

•β-foglietto distorto
•a forcina
•sup. convessa: idrofobica
•sup. concava: idrofilica
•ponte disolfuro vicinale

Molecola anfipatica
Regolazione della trascrizione
dell’epcidina
 Funzione biologica
Regolazione dell’epcidina a livello del trasporto transmembrana del ferro:

Target
dell’epcidina

La ferroportina

•Enterociti
•Epatociti
•Macrofagi

Nemeth E,et al.Hepcidin regulates cellular iron

efflux by binding to frroportin and inducing its
internalization.Science.2004;306:2090-93.
 Iron-dependent BMP signaling

Fleming, M. D. Hematology 2008;2008:151-158

Iron-dependent BMP signaling. Transferrin receptor 1 (TFR1), the autosomal recessive hereditary hemochromatosis
proteins HFE, transferrin receptor 2 (TFR2), and hemojuvelin (HJV) as well as the bone morphogenetic protein receptor type
I and II (BMPR I/II) complex are associated with the cell surface. HFE associates with TFR1 and TFR2 in an equilibrium
modified by the concentration of holotransferrin (TF). It has been suggested that HFE and TFR2 can further associate with
the HJV-BMPR I/II signaling complex to modify BMPR signaling mediated by phosphorylation upon sons of mothers against
decapentaplegic homologues (SMADs) 1, 5, and 8. Association of phosphorylated SMAD1/5/8 with a common co-SMAD,
SMAD4, leads to translocation of the complex into the nucleus and stimulation of hepcidin ( HAMP) gene expression.
Microcytic anemia and hepatic iron overload
in a child with compound heterozygous
mutations in DMT1 (SCL11A2

 Microcytic anemia and hepatic iron overload in a child with

compound heterozygous mutations in DMT1 (SCL11A2 The
proband required blood transfusions until erythropoietin
treatment allowed transfusion independence when
hemoglobin levels between 75 and 95 g/L (7.5 and 9.5 g/dL)
were achieved. Hematologic data of this patient at birth and in
the first years of life strengthen the essential role of DMT1 in
erythropoiesis. The early onset of iron overload indicates that,
as in animal models, DMT1 is dispensable for liver iron
uptake, whereas its deficiency in the gut is likely bypassed by
the up-regulation of other pathways of iron use.

Achille Iolascon, Maria d'Apolito, Veronica Servedio, Flora Cimmino,

Antonio Piga, and Clara Camaschella Blood, 1 January 2006, Vol. 107,
No. 1, pp. 349-354.
The human counterpart of zebrafish
shiraz shows sideroblastic-like
microcytic anemia and iron overload

 We report the first case of GLRX5 deficiency in

a middle-aged anemic male with iron overload
and a low number of ringed sideroblasts.
Anemia was worsened by blood transfusions
but partially reversed by iron chelation.

C. Camaschella, A. Campanella, L. De Falco, L. Boschetto, R. Merlini, L.

Silvestri, S. Levi, and A. Iolascon
Blood, August 15, 2007; 110(4): 1353 - 1358.
Two nonsense mutations in the
TMPRSS6 gene in a patient with
microcytic anemia and iron deficiency

 Here, we show that iron deficiency anemia

with poor intestinal absorption and defective
iron utilization of IV iron is caused by
inherited mutations in TMPRSS6, a liver-
expressed gene that encodes a membrane-
bound serine protease of previously unknown
role that was recently reported to be a
regulator of hepcidin expression.

F. Guillem, S. Lawson, C. Kannengiesser, M. Westerman, C. Beaumont,

and B. Grandchamp Blood, September 1, 2008; 112(5): 2089 - 2091

Divalent metal transporter 1 (DMT1) contributes to
neurodegeneration in animal models of Parkinson's
diseasePNAS 2008 105:18578-18583; published
online before print November 14, 2008,
doi:10.1073/pnas.0804373105
...A recent study on rat brain reported that the
expression of both the +IRE and IRE DMT1 isoforms
is not modulated by iron overload or deficiency and is
increased during aging (11), the main risk factor in PD.
On the other hand, in vitro studies in..
Bone morphogenetic proteins 2, 4, and 9
stimulate murine hepcidin 1 expression
independently of Hfe, transferrin receptor 2
(Tfr2), and IL-6.

...hepcidin expression and an impaired hepcidin

response to iron overload and IL-6. In addition,
these mice exhibited abnormal iron...previously
unrecognized target for therapeutic intervention
in iron overload disease and/or anemia of
chronic inflammation. We conclude...

PNAS 2006 103:10289-10293;