PHYSIOLOGY 21: 115–123, 2006; 10.1152/physiol.00052.
2005
The Ins and Outs of Iron Homeostasis
Iron is an essential element that is toxic when it accumulates in excess. Intricate reg-
ulatory mechanisms have evolved to maintain iron homeostasis within cells and
between different tissues of complex organisms. This review discusses the proteins
involved in iron transport and storage and their regulation in health and disease.
Iron is an essential metal, required as a co-factor in
proteins that transfer electrons and manage oxygen.
Until recently, there was little molecular understand-
ing of how mammalian tissues meet the challenge of
acquiring adequate amounts of iron without risking
the toxic effects of iron excess. Our current knowledge
of mammalian iron physiology and homeostasis is
painted in broad brushstrokes, with many details
remaining to be discovered. This review summarizes
recent progress in identifying key protein transporters
and the molecules that regulate their activities.
Although all cells need a small amount of iron, ery-
throid precursors require substantial amounts to pro-
duce hemoglobin. Accordingly, anemia is a prominent
manifestation of iron deficiency. Other cell types also
have specialized roles that are important to consider
in assembling a systemic model of iron homeostasis.
Intestinal epithelial cells (enterocytes), extraembryon-
ic visceral endoderm cells, and placental syncytiotro-
phoblasts serve in the acquisition of iron from the
external environment. Of these, iron handling by ente-
rocytes is best understood. Liver hepatocytes serve a
depot function, removing excess iron from circulating
plasma and safely storing it until it is needed. Tissue
macrophages recognize and phagocytose old and
damaged erythrocytes, recovering their iron for reuse
and storage. Molecular signals must coordinate the
operations of each of these cell types. To date, no effi-
cient, regulated excretion mechanism for iron has
been described, underscoring the importance of
meticulous regulation of iron acquisition and distribu-
tion.
Intestinal Iron Absorption
Mammals absorb dietary iron through the duodenal
epithelium of the small intestine (29, 66), which is
organized in villous structures to maximize its absorp-
tive surface area. Enterocyte precursors are present in
crypts at the bases of villi, migrating up the villous axis
as they differentiate. Membrane extensions at the api-
cal surface of enterocytes form a brush border that fur-
ther increases the surface area available for absorp-
tion. Mature enterocytes live for only 1–2 days. Iron
that accumulates within them is lost from the body
when senescent enterocytes are shed into the gut
lumen.
1548-9213/06 8.00 ©2006 Int. Union Physiol. Sci./Am. Physiol. Soc.
REVIEWS
Adriana Donovan,1* Cindy N.
Roy,1* and Nancy C. Andrews1,2
1Children’sHospital Boston, Dana-Farber Cancer Institute,
Harvard Medical School, and 2Howard Hughes Medical
Institute, Boston, Massachusetts
nancy_andrews@hms.harvard.edu
*A. Donovan and C. N. Roy contributed equally to this
work.
Proteins involved in the uptake of heme and inor-
ganic iron reside on the brush-border membrane
(FIGURE 1). Most non-heme iron in the diet is present
as the Fe3+ form. The major transporter involved in
cellular non-heme iron uptake (import) is divalent
metal transporter 1 (DMT1; also known as Nramp2,
DCT1, and SLC11A2), which has 12 predicted trans-
membrane segments (26, 33, 35). As its name implies,
DMT1 also transports other divalent metals including
Mn2+, Co2+, Cu2+, and Zn2+ (35). DMT1 is active in a
low-pH environment, as found in the duodenum,
because it requires proton cotransport (35). A require-
ment for DMT1 in intestinal iron absorption is clearly
supported by animal models with spontaneous and
induced mutations (20, 25, 26, 34). DMT1 exclusively
transports divalent metals, necessitating luminal con-
version of Fe3+ to Fe2+. McKie et al. (60) identified a
candidate intestinal iron reductase, duodenal
cytochrome b (Dcytb; also known as Cybrd1).
Expression of this putative transmembrane, di-heme
protein is induced in the intestinal mucosa of mice
with increased intestinal iron absorption due to ane-
mia, iron deficiency, or hypoxia (60). However, it was
recently reported that disruption of the murine Dcytb
gene did not significantly impair intestinal iron
absorption under normal conditions (36), suggesting
that other intestinal reductases may substitute or that
mice have an efficient mechanism for non-enzymatic
iron reduction.
The intestine also absorbs heme iron from the diet.
Cell-culture studies of the intestinal cell line Caco-2
suggested that heme absorption is a saturable, carrier-
mediated process (103). Other studies have described a
heme receptor on duodenal brush-border membranes
and erythroleukemia cells (28, 32). Recently, an entero-
cyte heme importer was described that likely mediates
dietary heme uptake (92). This molecule, termed heme
carrier protein 1 (HCP1), resembles bacterial proteins
that transport metal-tetracycline complexes. It has no
close mammalian homologs. Once dietary heme has
entered the intestinal epithelial cell, it is likely cleaved
by intracellular heme oxygenase 1 to release iron (85).
Subsequently, it probably joins the same intracellular
pool as non-heme iron. Two other proteins, FLVCR and
Bcrp, both function as cellular heme exporters (55, 84),
but neither has been shown to be involved in intestinal
heme transport.
115
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1 Dietary non-heme iron 2 DMT1 mediates proton- across the basolateral
(Fe3+) must be reduced for dependent Fe2+ import. membrane. A sponta-
transport across the apical
brush border. neous mouse mutant,
sex-linked anemia (sla),
Fe2+ Heme
has impaired iron
Fe3+
H+ DMT1 3 HCP1 transports absorption and accumu-
dietary heme iron. lation of iron in duodenal
Apical HCP1
enterocytes attributable
to a mutation in the gene
Ferri- encoding hephaestin (5,
reductase 82, 98). This phenotype is
(?Dcytb) similar to, but less severe
Heme
oxygenase than, the phenotype seen
in mice with intestine-
specific inactivation of
ferroportin (22).
4 Heme oxygenase releases Hephaestin is a mem-
Ferritin iron from protoporphyrin, brane-bound homolog of
allowing it to enter the same
pool as non-heme iron. the serum multi-copper
5 Some iron is used or stored oxidase ceruloplasmin
within the enterocyte in (40). The current model
ferritin, and is later lost suggests that hephaestin
when the intestinal
oxidizes Fe2+ released by
mucosa is sloughed.
ferroportin, facilitating
its incorporation into
Ferroxidase transferrin, the major
(hephaestin) serum iron carrier pro-
tein. The anemia of sla
mice resolves after the
Ferroportin Fe3+ neonatal period, sug-
Basolateral Fe2+
gesting that hephaestin is
primarily needed for iron
transfer during the accu-
6 Ferroportin exports some
iron, where it is oxidized to mulation of initial stores
Fe3+ for incorporation into and that serum cerulo-
serum transferrin. plasmin may substitute
later.
FIGURE 1. Intestinal iron absorption
An individual enterocyte is depicted. Dietary non-heme iron (Fe3+) must be reduced for
transport across the apical brush border. DMT1 mediates proton-dependent Fe2+ import. Intercellular and
Dietary heme iron is transported by HCP1. Once inside the cell, heme oxygenase releases Intracellular Iron
iron from protoporphyrin, presumably allowing it to enter the same pool as non-heme iron.
Some iron is used or stored within the enterocyte in ferritin. This iron is later lost from the
Handling
body when the intestinal mucosa is sloughed. Some iron is exported across the basolateral
membrane by ferroportin and oxidized to Fe3+ for incorporation into serum transferrin. Iron circulates bound to
Intracellular enterocyte iron can either be stored in the 80-kDa serum glycoprotein transferrin (TF), which
the multimeric protein ferritin (95) or transported has two high-affinity iron binding sites. Diferric TF
across the basolateral membrane of the enterocyte binds to a highly specific TF receptor (TFR1), allowing
into the circulation. Ferroportin (also known as cellular uptake by receptor-mediated endocytosis.
IREG1, MTP1, and SLC40A1), a distinct transporter The receptors collect in clathrin-coated pits and facil-
with 10–12 transmembrane segments, was identified itate transferrin internalization into endocytic vesi-
as a compelling candidate for the basolateral iron cles. The endosomes become acidified, likely through
exporter (1, 21, 61). Intestinal expression of ferroportin the pump action of an Na+-H+-ATPase (73). As the
mRNA and protein increases in response to iron defi- endosomes reach pH 5.5, acidification and protein
ciency and hypoxia (61). Recently, selective inactiva- conformation changes cause iron to dissociate from
tion of the murine ferroportin gene in intestinal cells TF (18). Fe3+ is reduced to Fe2+, likely by the endosomal
established that ferroportin is the major, if not only, reductase Steap3 (75), for transport from the endo-
intestinal iron exporter (22). Ferroportin is probably some to the cytoplasm by the transporter DMT1 (25).
also selective for Fe2+. Multicopper oxidases that oxi- DMT1 localizes to recycling endosomes through a sig-
dize Fe2+ to Fe3+ also play a role in the transport of iron nal found in one of two carboxy-termini generated by

116 PHYSIOLOGY • Volume 21 • April 2006 • www.physiologyonline.org


alternative splicing (56). The TF cycle is completed
when the endosome returns to and fuses with the plas-
ma membrane, returning apoTF to the circulation and
TFR1 to the plasma membrane and allowing both
molecules to start the cycle again.
Cellular iron in excess of immediate needs is stored
as an iron oxide solid within the central cavity of fer-
ritin, a polymeric protein composed of varying ratios
of heavy (H) and light (L) ferritin polypeptides (94). To
ensure that very little iron is free within cells, iron reg-
ulatory proteins (IRP1 and IRP2) control the posttran-
scriptional expression of genes modulating cellular
iron uptake and storage. Under low iron conditions,
both proteins bind to conserved, hairpin-like iron reg-
ulatory elements (IREs) present in the untranslated
regions (UTRs) of target mRNAs. Classical studies
defined the roles of IRPs and IREs in regulating
mRNAs encoding TFR1 and ferritin subunits. The
TFR1 mRNA contains five IRE elements in its 3’-UTR.
IRP binding protects the mRNA from endonucleolytic
degradation (42). Thus, when the cell is iron depleted,
more TFR1 protein is made, resulting in increased iron
acquisition. In contrast, binding of IRPs to the single
IREs in the 5’-UTRs of ferritin mRNAs does not affect
mRNA stability but rather inhibits translation of the
mRNA into protein (42). Accordingly, less ferritin pro-
tein is made when it is not needed for iron storage.
IRP1 and IRP2 activities are regulated by iron, but
through distinct mechanisms. IRP1 is inactivated by
the incorporation of a 4Fe•4S cluster, which converts
the protein into a cytoplasmic aconitase enzyme (38).
IRP2 is inactivated by iron-dependent degradation
(37, 47). In addition to interpreting cellular iron status,
IRP1 and IRP2 both respond to nitric oxide levels, IRP1
responds to H2O2, and IRP2 is regulated by hypoxia
(39, 42, 77).
Several other iron-related mRNAs also contain IRE
elements. A single IRE is present in the 3’-UTR of one
splice isoform of DMT1 mRNA (45). 5’-IREs are pres-
ent in mRNAs encoding the erythroid form of the
heme biosynthetic aminolevulinic acid synthase
(eALAS; Refs. 14, 17) and the iron transporter ferro-
portin (1, 21, 61). The 5’-IRE in the eALAS mRNA like-
ly serves to coordinate initiation of heme biosynthesis
with iron availability. The presence of IREs in DMT1
and ferroportin mRNAs suggests that their expression
may be controlled, at least in part, by cellular iron con-
tent. Although this is not yet understood in detail, evi-
dence for in vivo activity of the IRE in the ferroportin
mRNA comes from the spontaneous mouse mutant
polycythemia (pcm), which has a genomic deletion
that inactivates the ferroportin IRE, resulting in a com-
plex phenotype with transient polycythemia in het-
erozygotes (pcm/+) and iron deficiency anemia in
homozygotes (pcm/pcm) (63).
Data from multiple animal models establish that the
TF cycle is critical for iron uptake into erythroid cells
(6, 20, 25, 26, 34, 58, 102). In addition, human muta-
REVIEWS
tions associated with anemia have been identified in
both the TF and DMT1 genes (7, 46, 62). However,
studies of non-erythroid cells indicate that there must
be distinct mechanisms for non-TF-bound iron
(NTBI) uptake. Although the proteins normally
involved in this process have not been identified (9),
two possible mechanisms for mammalian NTBI
uptake have been described.
Purified lipocalin 2 (also known as Ngal and 24p3)
(30, 106) contains iron complexed in bacterial
siderophores. It is not yet clear whether this form has a
physiological role in iron transport. Nonetheless, the
complex is taken up by cells through an as yet uniden-
tified receptor-mediated process. To date, studies
implicate the iron-binding activity of lipocalin 2 in
early renal development and in innate immunity, but
further study will be necessary to determine whether it
plays a general role in NTBI uptake (27, 106).
L-type calcium channels have also been implicated
in NTBI uptake. Mammals express four highly homol-
ogous L-type calcium channels (Cav1.1-1.4). L-type cal-
cium channels have been shown to mediate cellular
iron uptake in vitro (96) and to be involved in iron dep-
osition in the murine heart in the setting of iron over-
load in vivo (76). Pharmacological calcium channel
blockers interfere with this activity. Interestingly, the
spontaneous mk mutation in murine DMT1 effective-
ly converts the iron transporter to an efficient calcium
channel, consistent with the idea that similar trans-
membrane pores conduct Fe2+ and Ca2+ (104). L-type
calcium channels are widely expressed and thus could
be involved in NTBI uptake in other tissues.
Iron Utilization and Recovery
Hemoglobin production in erythroid precursors is a
complex process requiring meticulous coordination of
iron acquisition, protoporphyrin biosynthesis, and
globin protein production. Perturbation of this bal-
anced process invariably results in disease. Disorders
of hemoglobin synthesis give insight into iron home-
ostasis.
The protoporphyrin precursor of heme is construct-
ed through a series of enzymatic reactions that take
place alternately in the mitochondrion and the cyto-
plasm. Mutations in the enzymes involved in heme
biosynthesis lead to a spectrum of diseases, several of
which have iron phenotypes. Mutations in the first
enzyme, ALAS2, result in sideroblastic anemia (15),
characterized by accumulation of unused iron in the
mitochondria of erythroid precursors, likely in the
form of mitochondrial ferritin (11). The final enzyme
of heme biosynthesis, ferrochelatase, introduces iron
into protoporphyrin IX to produce heme (16).
Mutations in this protein result in erythropoietic pro-
toporphyria, a rare disease resulting from accumula-
tion of protoporphyrin lacking iron (12, 89, 91, 97).
These patients can also have sideroblasts, similar to
PHYSIOLOGY • Volume 21 • April 2006 • www.physiologyonline.org 117
REVIEWS
patients with ALAS2 mutations. Sideroblastic anemia per oxidase, facilitates movement of iron out of tissue
can also result from mutations in proteins with less stores and into TF (40, 41).
direct roles in heme biosynthesis (24). For example, X-
linked sideroblastic anemia with spinocerebellar atax- Systemic Regulation and Regulatory
ia results from mutations in the mitochondrial trans- Factors
porter ABC7 (4), which is required for the maturation
of cytosolic iron sulfur (Fe•S) clusters. Control of iron balance in the whole organism requires
Recycling of iron from senescent erythrocytes pro- communication between sites of uptake, utilization,
vides most of the iron utilized by developing red blood and storage. In recent years, hepcidin (encoded by the
cells. Specialized macrophages in the spleen, bone HAMP gene) has emerged as a primary regulator of
marrow, and liver remove effete red cells from circula- iron homeostasis. Hepcidin is a circulating peptide
tion for recovery of their iron. Neither the signal on the secreted by hepatocytes (54, 79, 81) that binds to fer-
effete erythrocyte nor the macrophage receptor has roportin at the cell surface to initiate ferroportin inter-
been clearly identified to date, but several promising nalization and degradation (69). In the duodenal ente-
candidates have been described. Accumulation of rocyte, hepcidin-dependent regulation of ferroportin
phosphatidylserine in the outer leaflet of the erythro- reduces dietary iron absorption. In the macrophage
cyte membrane seems to be a primary event (13), but (and possibly the hepatocyte), hepcidin activity atten-
Ca2+ flux (57), removal of sialic acids on the cell sur- uates cellular iron release. Loss of hepcidin protein
face, and opsonization of red blood cells by autoanti- results in severe iron overload in mice (70) and human
bodies are all possible signals for turnover (8). The patients (78, 88), underscoring the central role of hep-
scavenger receptor CD36 (53, 93) is a plausible candi- cidin in regulating iron balance.
date for the macrophage-specific receptor. Consistent with its role as a negative regulator of
After the red cell has been internalized into an iron absorption, hepcidin expression is decreased in
acidic phagosome, heme oxygenase liberates iron response to anemia and hypoxia (71) (FIGURE 2).
from heme (83). The iron is likely transferred out of the This is advantageous, because it makes more iron
phagosome by DMT1 (48) for cellular storage or return available for erythropoiesis. In contrast, hepcidin
to the serum. The factors that influence whether the expression is increased in response to inflammation
macrophage retains or releases iron are not known, (67) and nongenetic iron overload (81). This response
but intracellular iron content (99), cytokine activity minimizes the availability of iron, inhibiting the
(86, 101), and reactive oxygen species such as nitric growth of pathogens and limiting the iron burden.
oxide (31) may be involved. Iron egress from Neither the factor that induces hepcidin in response to
macrophages is partly, if not entirely, mediated by fer- iron loading nor the factor that inhibits hepcidin in
roportin (22, 105). Ceruloplasmin, a serum multicop- response to anemia or hypoxia has been identified.
The unidentified ery-
NEGATIVE REGULATORS POSITIVE REGULATORS throid suppressor of hep-
cidin expression appears
Hypoxia Iron
overload to overcome the putative
sensor for iron loading,
Hepatocyte ?Fe2-TF
however, because hep-
cidin expression is sup-
Nucleus Mutations in HFE,
Soluble HJV TFR2, HJV, and HAMP pressed in anemias com-
result in decreased plicated by iron overload
hepcidin expression. such as hypotransfer-
rinemia (100) and tha-
HAMP lassemia (2). Although
IL-6
we have a general knowl-
Increased Inflammation edge of the conditions
erythroid drive that regulate hepcidin
HAMP = hepcidin gene expression, little is
known about the molec-
FIGURE 2. Regulation of hepcidin expression ular mechanisms of hep-
Hepatic production of the peptide hormone hepcidin is influenced by iron needs and cidin regulation. The dis-
stores. Anemia and hypoxia result in decreased hepcidin synthesis; inflammation, the covery of such factors
inflammatory cytokine interleukin-6 (IL-6), and increased iron stores (possibly through difer-
ric-TF) result in increased hepcidin synthesis. The molecular pathways involved in signal
will probably result from
transduction in response to these conditions have not yet been elucidated. The protein studies of hepatocytes,
products of hemochromatosis disease genes (HFE, TFR2, and HJV) are presumed to act as where several membrane
regulators of hepcidin expression because mutations in each result in inadequate hepcidin
production. A soluble cleavage product of HJV (sHJV) also has been shown to inhibit hep-
proteins (HFE, TFR2, and
cidin production. HJV) have already been

118 PHYSIOLOGY • Volume 21 • April 2006 • www.physiologyonline.org

 REVIEWS
NORMAL REGULATION HEMOCHROMATOSIS

Fe Fe

DMT1 DMT1

Ferritin
1 Under normal conditions,
circulating hepcidin regulates
cellular iron export by binding
to ferroportin and inducing
its degradation in lysosomes. Lysosome

Lysosomal
degradation
of ferroportin Enterocyte

Hepcidin Ferroportin
Fe
2 In balance, some iron is 3 In hemochromatosis, hepcidin is
retained within enterocytes deficient or absent, resulting in
and macrophages and some increased ferroportin on the cell
iron is exported into the serum. surface and accelerated iron release.

Macrophage

Fe Ferroportin Lysosomal
4 Consequently, intestinal
degradation
iron absorption is
of ferroportin
increased and serum
iron levels rise.

FIGURE 3. The hepcidin-ferroportin axis

In hemochromatosis, hepcidin is deficient or absent, resulting in increased ferroportin on the cell surface and acceler-
ated iron release. Consequently, intestinal iron absorption is increased and serum iron levels rise.

implicated in the modulation of hepcidin expression
in vivo. Homozygous or compound heterozygous
mutations in any of these three proteins result in
genetic hemochromatosis, a common iron-overload
disorder in human populations.
HFE is an atypical major histocompatibility class I
protein that is mutated in the majority of patients with
hemochromatosis (23). Mice (3, 65) and humans (10)
deficient in HFE have reduced hepatic expression of
hepcidin despite iron overload. HFE is highly
expressed in hepatocytes and is also expressed in
Kupffer cells (107). The physiologically significant site
of HFE expression remains controversial. The fact that
HFE forms a protein complex with TFR has led to the
attractive hypothesis that a soluble factor such as
diferric TF (which competes with HFE for TFR bind-
ing) might modulate HFE activity and regulate a
potential pathway signaling to the hepcidin (HAMP)
promoter. To date, direct evidence supporting this
hypothesis is lacking.
Transferrin receptor 2 (TFR2; a homolog of TFR) is
mutated in a small subset of patients with genetic
hemochromatosis. Its normal function is unclear.
However, like HFE, deficiency of TFR2 attenuates hep-

PHYSIOLOGY • Volume 21 • April 2006 • www.physiologyonline.org 119

REVIEWS
cidin expression in mice (50) and humans (68) and
results in moderate iron overload. TFR2 is highly
expressed in hepatocytes (52) but is also expressed in
erythroblasts (51). No erythropoietic abnormalities
have been observed in mice or humans with TFR2
deficiency, suggesting that the TFR2 requirement for
hepcidin regulation is intrinsic to the hepatocyte and
not the result of feedback through the anemia/hypox-
ia regulatory pathway. Diferric TF is also an attractive
candidate for communicating iron status to regulate
hepcidin expression via TFR2 as TF induces TFR2
expression in hepatocytes (49, 87).
Hemojuvelin (HJV) is a homolog of proteins
involved in neural patterning. It was recently
described as a hemochromatosis disease gene (78).
HJV deficiency in mice (43, 72) and humans (44, 78)
reduces hepcidin levels further than either HFE or
TFR2 deficiency and, accordingly, results in more
severe iron loading. HJV is expressed in a number of
tissues including liver, heart, and skeletal muscle, and
found in plasma in a soluble form. Recent data suggest
that cell-associated HJV is required for normal expres-
sion of hepcidin in hepatocytes and that soluble HJV
negatively regulates hepcidin expression in hepato-
cytes (59). The cellular source of soluble HJV and the
conditions that regulate its production are currently
unknown, but high expression of HJV in skeletal and
cardiac muscle suggests that these iron-rich tissues
may communicate their iron needs through soluble
HJV.
Induction of hepcidin in response to inflammation
is mediated, at least in part, by interleukin-6 (IL-6) (67)
(FIGURE 2). The relationship between IL-6 induction
of hepcidin expression and regulation by HFE, TFR2,
and HJV remains uncertain. Hepcidin induction caus-
es hypoferremia through cellular iron-withholding, a
response that contributes to innate immunity (67).
However, there is a co-existing deleterious effect.
Increased hepcidin levels also restrict the availability
of iron for erythropoiesis, resulting in the anemia of
inflammation, a common disorder observed in
patients with inflammation, infection, organ failure, or
recent trauma.
Pathogenesis of Iron-Overload
Disorders
Studies focused on the regulation of iron homeostasis
have converged on hepcidin as a common effector
molecule, acting through its modulation of ferroportin
activity (FIGURE 2). All known heritable disorders of
iron overload involve mutations affecting hepcidin
itself, regulators of hepcidin (HFE, TFR2, HJV), or the
hepcidin target ferroportin.
Patients with mutations in HFE and TFR2, pre-
sumed regulators of hepcidin expression, generally
present in midlife with elevated transferrin saturation,
parenchymal iron loading, and proportionally less
120 PHYSIOLOGY • Volume 21 • April 2006 • www.physiologyonline.org
iron in tissue macrophages (80). Each of these features
can be explained by modest hepcidin deficiency in
these individuals. Without hepcidin, there is inade-
quate regulation of ferroportin at the basolateral sur-
face of enterocytes, contributing to increased dietary
iron uptake. Likewise, ferroportin activity remains ele-
vated in macrophages, explaining their relative iron
deficiency (FIGURE 3).
Patients with mutations in hepcidin and HJV pres-
ent in the second or third decade of life with elevated
transferrin saturation and severe iron loading. The
clinical picture is dominated by cardiomyopathy and
endocrinopathies. If untreated, iron-related organ
damage is lethal by the fourth decade of life. Their
hepcidin levels are lower than those in patients with
HFE or TFR2-related hemochromatosis, consistent
with the accelerated iron loading in these individuals.
Mutations in ferroportin result in either of two dis-
tinct iron overload diseases, each inherited in an auto-
somal-dominant pattern (19, 64, 74, 90). Similar to
other forms of hemochromatosis, some patients pres-
ent with parenchymal iron overload and elevated
transferrin saturation. These patients have mutant fer-
roportin that is expressed at the cell surface and is
capable of iron egress but resistant to regulation by
hepcidin. In contrast, other ferroportin mutations
cause mislocalization and/or loss of transporter func-
tion. These patients have little or no parenchymal iron
loading and low to normal serum iron levels, but tissue
macrophages are iron-laden.
Future Directions
Now that most of the key proteins involved in iron
homeostasis have been identified, future investiga-
tions must focus on understanding their molecular
functions. To date, there have been few structural
studies of DMT1, ferroportin, or HCP1, and it is not yet
known how they carry out transmembrane iron trans-
port. Although the stimuli that modulate hepcidin
expression are well described as phenomena, we do
not yet understand how physiological signals are
transduced to regulate hepcidin production. The
potent erythroid suppressor of hepcidin synthesis has
not yet been identified. The detailed molecular activi-
ties of hemochromatosis disease proteins HFE, TFR2,
and HJV have not yet been reported. Undoubtedly, the
next decade should yield a more comprehensive
understanding of iron metabolism and likely inform
other studies of the whole organism.

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