http://www.ncbi.nlm.nih.

gov/pmc/articles/PMC2516548/ body iron meth yutaka

Normal Iron Absorption and Storage
Iron facts

All body cells need iron. It is crucial for oxygen transport, energy production,
and cellular growth and proliferation.

The human body contains an average of 3.5 g of iron (males 4 g, females 3 g).

The typical daily American diet contains 1020 mg of iron.

Only about 10% of dietary iron is absorbed (12 mg/day).

Iron absorption

Iron is mainly absorbed in the duodenum and upper jejunum.

A protein called divalent metal transporter 1 (DMT1) facilitates iron transfer

across intestinal epithelial cells.

Normally, individuals absorb less than 10% of dietary iron, or 12 mg per day
balancing the daily loss from desquamation of epithelia.

Most absorbed iron is used in bone marrow for erythropoiesis.

Iron homeostasis is closely regulated via intestinal absorption.

Once iron is absorbed, there is no physiologic mechanism for excretion of excess

iron from the body other than blood loss (i.e., pregnancy, menstruation or other
bleeding.)

Iron transport

Most absorbed iron is transported in the bloodstream bound to the glycoprotein

transferrin.

Transferrin is a carrier protein that plays a role in regulating the transport of iron
from the site of absorption to virtually all tissues.

Transferrin binds only two iron atoms.

Normally, 2045% of transferrin binding sites are filled (measured as percent

transferrin saturation [TS]).

Normal Iron Absorption and

Metabolism

Iron is bound and transported in the body via

transferrin and stored in ferritin molecules.
Once iron is absorbed, there is no physiologic
mechanism for excretion of excess iron from the
body other than blood loss i.e., pregnancy,
menstruation or other bleeding.
Iron use in the body

75% of absorbed iron is bound to proteins such as hemoglobin that are involved
in oxygen transport.

About 10% to 20% of absorbed iron goes into a storage pool that is also
recycled in erythropoiesis, so storage and use are balanced.

Iron storage

Iron is initially stored in ferritin molecules.

A single ferritin molecule can store up to 4,000 iron atoms.

When excess dietary iron is absorbed, the body responds by producing more
ferritin to facilitate iron storage.

Ferritin Storage Molecule

Ferritin molecules store thousands of iron

atoms within their mineral core. When excess
dietary iron is absorbed, the body responds
by producing more ferritin to facilitate iron
storage.

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Iron Transport and Cellular Uptake

Iron kinetics

Only a small proportion of total body

iron daily enters or leaves the body's
stores on a daily basis (Figure1).
Consequently, intercellular iron
transport, as a part of the iron
reutilization process, is quantitatively
more important that intestinal
absorption. The greatest mass of iron
is found in erythroid cells, which
contain about 80% of the total body
endowment. The reticuloendothelial
system recycles a substantial amount
of iron from effete red cells,
approximating the amount used by the
Figure 1. Iron is assiduously
erythron for new hemoglobin
conserved and recycled for use
production.
in heme and non-heme

Transferrin

enzymes. About 1 to 2 mg of
iron are lost each day to
sloughing of skin and mucosal
cells of the gastrointestinal and
genitouretal tracts. This
obligate iron loss is balanced by
iron absorption from the
gastrointestinal tract. Only a
small fraction of the 4 grams of
body iron circulate as part of
transferrin at any given time.
Body iron is most prominently
represented in hemoglobin and
in ferritin.

Of the approximate 3 grams of body

iron in the adult male, approximately
3mg or 0.1% circulates in the plasma
as an exchangeable pool (Table 1).
Essentially all circulating plasma iron
normally is bound to transferrin. This
chelation serves three purposes: it
renders iron soluble under physiologic
conditions, it prevents iron-mediated
free radical toxicity, and it facilitates transport into cells.
Transferrin is the most important physiological source of iron for
red cells (Ponka, 1997). The liver synthesizes transferrin and
secretes it into the plasma. Transferrins are produced locally in
the testes and CNS. These two sites are relatively inaccessible to
proteins in the general circulation (blood:testis barrier,
blood:brain barrier). The locally synthesized transferrin could play
a role in iron metabolism in these tissues. Information on the
function of transferrin produced in these localized sites is sparce,

however.

Plasma transferrin is an 80 kDa glycoprotein with homologous N-terminal and Cterminal iron-binding domains (reviewed in Huebers and Finch, 1987]. The
molecule is related to several other proteins, including ovotransferrin in bird and
reptile eggs (Williams et al., 1982), lactoferrin in extracellular secretions and
neutrophil granules (Mazurier et al., 1983); (Metz-Boutigue et al., 1984) and
melanotransferrin (p97), a protein produced by melanoma cells (Brown et al.,
1982). Ovotransferrin may help protect the developing embryo in the semipermeable egg by sequestering iron that microbes need to grow. Lactoferrin, in
secretions such as milk and tears, might have a similar function. One recent report
indicates that lactoferrin can act as a site-specific DNA binding protein, and could
mediate transcriptional activation. Such a function is, however, at odds with its
existence as an extracellular protein (He and Furmanski, 1995).
X-ray crystal structures exist for human lactoferrin and rabbit transferrin
(reviewed by [Baker and Lindley, 1992]. All members of the transferrin protein
superfamily have similar polypeptide folding patterns. N-terminal and C-terminal
domains are globular moieties of about 330 amino acids; each of these is divided
into two sub-domains, with the iron- and anion-binding sites in the intersubdomain
cleft. The binding cleft opens with iron release, and closes with iron binding. Nand C-terminal binding sites are highly similar.
Iron binding by Transferrin

The precise mechanics of iron loading onto transferrin as it

leaves intestinal epithelial cells or reticuloendothelial cells is
unknown. The copper-dependent ferroxidase, ceruloplasmin, may
play a role. Compelling evidence indicates that the protein is
involved in mobilizing tissue iron stores to produce diferric
transferrin (Osaki and Johnson, 1969); (Osaki et al., 1971);
(Yoshida et al., 1995); (Harris et al., 1995).
Transferrin binds iron avidly with a dissociation constant of approximately 10 22 M1
(Aisen and Listowsky, 1980). Ferric iron couples to transferrin only in the
company of an anion (usually carbonate) that serves as a bridging ligand between
metal and protein, excluding water from two coordination sites (Aisen and
Listowsky, 1980); (Harris and Aisen, 1989); (Shongwe et al., 1992). Without the
anion cofactor, iron binding to transferrin is negligible. With it, ferric transferrin is

resistant to all but the most potent chelators. The remaining four coordination sites
are provided by the transferrin protein - a histidine nitrogen, an aspartic acid
carboxylate oxygen, and two tyrosine phenolate oxygens (Bailey et al., 1988);
(Anderson et al., 1989). Available evidence suggests that anion-binding takes place
prior to iron-binding. Iron release from transferrin involves protonation of the
carbonate anion, loosening the metal-protein bond.
Table 1. Distribution Transferrin/Iron Physiology
and Kinetics of Body
The sum of all iron binding
Iron
Compart
ment
Hemoglobi
n
Myoglobin
Heme
Enzymes
Non-heme
Enzymes
Intracellul
ar Storage
(Ferritin)
Intracellul
ar Labile
Iron
(Chelatabl
e Iron)

sites on
transferrin constitutes the total iron binding
Iron Perce
capacity (TIBC) of plasma. Under normal
(gra nt of
ms) Total circumstances, about one-third of transferrin
iron-binding pockets are filled. Consequently,
2.7
66 with the exception of iron overload where all
the transferrin binding sites are occupied,
non-transferrin-bound iron in the circulation is
0.2
3
virtually nonexistent. Distribution of plasma
59
0.008 0.1 and tissue iron can be traced using Fe as a
radioactive tag. The subject receives
<
autologous transferrin loaded with radioactive
0.000 --- iron that then can be monitored. Blood
1
samples can be analyzed at timed intervals to
determine the rate of loss of the radioactive
1.0
30 label. Such ferrokinetic studies indicate that
the normal half-life of iron in the circulation is
about 75 minutes (Huff et al., 1950). The
absolute amount of iron released from
0.07
1
transferrin per unit time is the plasma iron
(?)
turnover (PIT).

Such radioactive tracer studies indicate that at least

eighty percent of the iron bound to circulating transferrin
is delivered to the bone marrow and incorporated into
newly formed erythrocytes (Jandl and Katz, 1963); (Finch
et al., 1982); Fig. 1). Other major sites of iron delivery
include the liver, which is a primary depot for stored iron,
and the spleen. Hepatic iron is found in both reticuloendothelial cells and
hepatocytes. Reticuloendothelial cells acquire iron primarily by phagocytosis and
breakdown of aging red cells These cells extract the iron from heme and return it to

Intercellula
r
Transport 0.003 0.1
(Transferri
n)

the circulation bound to transferrin. Hepatocytes take up iron by at least two

different pathways. The first involves receptor-mediated endocytosis of transferrin.
In addition, hepatocytes can take up ionic iron by a process independent of
transferrin (Inman and Wesling-Resnick, 1993).
Ferrokinetics and the Bone Marrow

Given the preeminent role of the bone marrow in the clearance of

labeled iron from the circulation, ferrokinetics provide a window
on erythropoietic activity. Conditions that augment erythrocyte
production increase the PIT. For example, hemolytic anemias such
as hereditary spherocytosis and sickle cell disease induce rapid
delivery of transferrin-bound iron to the marrow. In contrast,
disorders that reduce red cell production prolong the PIT. This
picture is seen, for example, with anemia due to Diamond
Blackfan anemia.
When erythrocytes are produced and released into the circulation in a normal
fashion, the process of erythropoiesis is termed "effective". In patients with certain
hemolytic anemias, however, the nascent red cells are so abnormal they are
destroyed before leaving the marrow cavity. In this circumstance, the
erythropoiesis is "ineffective", meaning simply that the erythropoietic precursors
have failed to accomplish their primary task: the delivery of intact erythrocytes to
the circulation. The ferrokinetic profiles such cases show rapid removal of iron
from transferrin with a delayed entry of label into the pool of circulating red cell
hemoglobin. +-thalassemia is an important example of this pattern of hemolytic
anemia with ineffective erythropoiesis. In +-thalassemia, ineffective erythropoiesis
is coupled with a markedly enhanced PIT.
Cellular Iron Uptake

Although transferrin was characterized fifty years ago (Laurell

and Ingelman, 1947), its receptor eluded investigators until the
early 1980s. In a quest to better understand the behavior of
neoplastic cells, investigators prepared monoclonal antibodies
against tumor cells. The target of these monoclonal antibodies
later was found to be the cell surface transferrin receptor
glycoprotein (Sutherland et al., 1980; Seligman et al., 1980).
A broad body of literature now supports the concept that the iron-transferrin
complex is internalized by receptor-mediated endocytosis. The general structure of

the transferrin receptor is shown in Figure 2. This disulfide-linked homodimer has

subunits containing 760 amino acids each (Kuhn Schematic representation of
et al., 1984); (Schneider et al., 1983); (Jing and
the transferrin receptor
Trowbridge, 1987). Oligosaccharides account for
about 5% of the 90 kDa subunit molecular mass
(Reckhow and Enns, 1988). Four glycosylation
sites (three N-linked and one O-linked) line the
protein (Hayes et al., 1992). Glycosylationdefective mutants have fewer disulfide bridges,
bind transferrin less efficiently and are expressed
less prominently on the surface expression than
are normal receptors (Williams and Enns,
1993a); (Williams and Enns, 1993b).

The transmembrane domain, between amino

acids 62 and 89, functions as an internal signal
peptide, as none exits at the N-terminal end
(Zerial et al., 1986). A molecule of fatty acid
(usually palmitate) covalently links each subunit
to the internal edge of the transmembrane
Figure 2. The molecule is a
domain and could play a role in membrane
transmembrane homodimer
localization. Interestingly, non-acylated mutants
linked by disulfide bonds. An
mediate faster iron uptake than normal receptors acyl group attached to the
(Alvarez et al., 1990); (Jing and Trowbridge,
cytoplasmic tail of the molecule
anchors the assembly to the
1990). The transferrin binding regions of the
plasma membrane.
protein are unidentified (Williams and Enns,
1993a); (Williams and Enns, 1993b). Efforts to
crystallize transferrin receptor protein are underway.
Iron is taken into cells by receptor-mediated endocytosis of monoferric and
diferric transferrin (Karin and Mintz, 1981); (Klausner et al., 1983); (Iacopetta and
Morgan, 1983); (Fig. 3). Receptors on the outer face of the plasma membrane bind
iron-loaded transferrin with a very high affinity. The C-terminal domain of
transferrin appears to mediate receptor binding (Zak et al., 1994). Diferric
transferrin binds with higher affinity than monoferric transferrin or apotransferrin
(Huebers et al., 1984); (Young et al., 1984). The dissociation constant (Kd) for
bound diferric transferrin ranges from 10-7 M to 10-9 M at physiologic pH,
depending on the species and tissue assayed (Stein and Sussman, 1983); (Sawyer

and Krantz, 1986). The Kd of monoferric transferrin is approximately 10 -6M. The

concentration of circulating transferrin is about 25 M. Therefore, cellular
transferrin receptors ordinarily are fully saturated.
After binding to its receptor on the cell surface, transferrin is rapidly internalized
by invagination of clathrin-coated pits with formation of endocytic vesicles (Figure
3). This process requires the short, 61 amino acid
Receptor-mediated
transferrin endocytosis
intracellular tail of the transferrin receptor
molecule (Rothenberger et al., 1987); (Alvarez et
al., 1990); (McGraw and Maxfield, 1990);
(Girones et al., 1991); (Miller et al., 1991).
Receptors with truncated N-terminal cytoplasmic
domains do not recycle (Rothenberger et al.,
1987). This portion of the molecule contains a
conserved tyrosine-threonine-argininephenylalanine (YTRF) sequence which functions
as a signal for endocytotic internalization
(Collawn et al., 1993). Genetically engineered
addition of a second YTRF sequence enhances
receptor endocytosis (Collawn et al., 1993). A
number of stimuli reversibly phosphorylate the
serine residue adjacent to the YTRF sequence, at
position 24 by the action of protein kinase C
(Davis et al., 1986). The role of receptor
phosphorylation is unclear. Despite removal of
the phosphorylation site by site-directed
mutagenesis, the transferrin receptor recycles
normally (Rothenberger et al., 1987).
Figure 3. Ferro-transferrin
binds to transferrin receptors on
the external surface of the cell.
The complex is internalized into
an endosome, where the pH is
lowered to about 5.5. Iron
separates from the transferrin
molecule, moving into the cell
cytoplasm. Here, an iron
transport molecule shuttles the
iron to various points in the cell,
including mitochondria and
ferritin. Ferritin molecules
accumulate excess iron.
Lysosomes engulf aggregates of
ferritin molecules in a process
termed "autophagy".

An ATP-dependent proton pump lowers the pH

of the endosome to about 5.5 (Van Renswoude et
al., 1982); (Dautry-Varsat et al., 1983); (Paterson
et al., 1984); (Yamashiro et al., 1984). The
acidification of the endosome weakens the
association between iron and transferrin. Even at
pH 5.5, Fe3+ would not normally dissociate from
transferrin in the several minutes between its
endocytosis and the return of transferrin

apoprotein to the cell surface (Ciechanover et al., 1983). A plasma membrane

oxidoreductase reduces transferrin bound iron from the Fe 3+ state to Fe2+, directly
or indirectly facilitating the removal of iron from the protein (Low et al., 1987);
(Thorstensen and Romslo, 1988); (Nunez et al., 1990). Conformational changes in
the transferrin receptor also play a role in iron release (Bali et al., 1991); (Sipe and
Murphy, 1991).
Rather than entering lysosomes for degradation, as do ligands in other receptormediated endocytosis pathways, intact receptor-bound apotransferrin recycles to
the cell surface, where neutral pH promotes detachment into the circulation (Zak
and Aisen, 1990). Thus the preservation and re-use of transferrin are accomplished
by pH-dependent changes in the affinity of transferrin for its receptor (Van
Renswoude et al., 1982); (Klausner et al., 1983); (Dautry-Varsat et al., 1983).
Exported apotransferrin binds additional iron and undergoes further rounds of iron
delivery to cells. The average transferrin molecule, with a half-life of eight days,
may be used up to one hundred times for iron delivery (Harford et al., 1994).
Topologically, the cell exterior and the endosome interior are equivalent
compartments. The primary role of the transferrin-transferrin receptor interaction is
to bring iron into the vicinity of the cell surface, thereby increasing the likelihood
of iron uptake. Following its release from transferrin within the endosome, iron
must traverse the plasma membrane to enter the cytosol proper. The molecules
effecting this transport have not been identified, but the process may be carriermediated (Egyed, 1988). Two anemic, mutant animals, the Belgrade rat (b/b) and
the hemoglobin deficit mouse (hbd/hbd) appear to have lesions at or near this step.
Their cells take up ferrotransferrin into endosomes, but fail to release iron into the
cytoplasm (Garrick et al., 1987); (Garrick et al., 1993). The molecular basis of the
defects in these animals have not been elucidated.
The endosomal transporter may reside on the plasma membrane of the cell prior to
endocytosis (Pollack, 1992). If so, it should be oriented to transport iron directly
into the cell, without the assistance of transferrin. Such non-transferrin-bound iron
uptake activities have been characterized in tissue culture. This uptake system
could function constitutively but inefficiently. Coupling the transferrin cycle to
transport across the plasma membrane might augment iron uptake by creating an
iron-rich environment for the transporter within the endosome. This same elusive
transport molecule could also be involved in intestinal iron uptake. The phenotype
of the mk/mk mouse (see above) suggests that red cell iron uptake and intestinal

iron uptake share a common component which could be the 'endosomal'

transporter.
Once inside the cell cytoplasm, iron appears to be bound by a low molecular
weight carrier molecule, which may assist in delivery to various intracellular
locations including mitochondria (for heme biosynthesis) and ferritin (for storage).
The identity of the intracellular iron carrier molecule(s) remains unknown. The
amount of iron in transit within the cell at any given time is minuscule and defies
precise measurement. This minute pool of transit iron, which is believed to be in
the Fe2+ oxidation state, is the biologically active form of the element.
Metabolically inactive iron, stored in ferritin and hemosiderin, is in equilibrium
with exchangeable iron bound to the low molecular weight carrier molecule
(Figure 3).
Both prokaryotes and eukaryotes produce ferritin molecules for iron storage.
Ferritins are complex twenty-four subunit heteropolymers of H (for heavy or heart)
and L (for light or liver) protein subunits (Theil, 1987). L subunits are 19.7 kDa in
mass, with isoelectric points of 4.5-5.0; H subunits are 21 kDa with isoelectric
points of 5.0-5.7. The subunits of the ferritin molecule form a sphere with a central
cavity in which up to 4500 atoms of crystalline iron is stored in the form of polyiron-phosphate oxide (Theil, 1987). Eight channels through the sphere are lined by
hydrophilic amino acid residues (along the three-fold axes of symmetry) and six
more are lined by hydrophobic residues (along the four-fold axes; [Harrison et al.,
1986].) Strong interspecies amino acid conservation exists in the residues that line
the hydrophilic channels, while marked variation exists in those along the
hydrophobic passages. Hydrophilic channels terminate with aspartic acid and
glutamic acid residues , and are lined by serine, histidine and cysteine residues (all
of which potentially bind metal ligands). The evolutionary conservation of the
hydrophilic channels suggests that they provide the route for iron entry and exit
from the ferritin shell, but this contention remains unproved. Little is known about
how iron is released from ferritin for use.
Although the two ferritin chains are highly homologous, only H ferritin has
ferroxidase activity. A mechanism involving dioxygen converts ferrous to ferric
iron, promoting incorporation into ferritin (Levi et al., 1988); (Lawson et al.,
1991). The composition of ferritin shells varies from H-subunit homopolymers to
L-subunit homopolymers, and includes all possible combinations between the two.
Isoelectric focusing of ferritin from a particular tissue reveals multiple bands
representing shells with different subunit compositions. These isoferritins, as they

are called, show tissue specific variation (Drysdale, 1988). Ferritin from liver, for
instance, is rich in L-subunits, as is that from the spleen. In contrast, the heart has
ferritin rich in H-subunits. Increased H subunit content correlates with increased
iron utilization, while increased L subunit content correlates with increased iron
storage (Drysdale, 1988); (Theil, 1987). The H:L ratio rises with activation of
heme synthesis or cell proliferation (Pattanapanyasat et al., 1987); (McClarty et al.,
1990). Ferritin thus provides a flexible reserve of iron.
Ferritin molecules aggregate over time to form clusters, which are engulfed by
lysosomes and degraded (Iancu et al., 1977); (Bridges, 1987); Figure 3). The endproduct of this process, hemosiderin, is an amorphous agglomerate of denatured
protein and lipid interspersed with iron oxide molecules (reviewed by (Wixom et
al., 1980). In cells overloaded with iron, lysosomes accumulate large amounts of
hemosiderin which can be visualized by Prussian blue staining. Although the iron
enmeshed in this insoluble compound constitutes an endstage product of cellular
iron storage, it remains in equilibrium with soluble ferritin. Ferritin iron, in turn, is
in equilibrium with iron complexed to low molecular weight carrier molecules.
Therefore the introduction into the cell of an effective chelator captures iron from
the low molecular weight "toxic iron" pool, draws iron out of ferritin, and
eventually depletes iron from hemosiderin as well, though only very slowly. As
might be expected, the bioavailability of hemosiderin iron is much lower than that
of iron stored in ferritin.

Non-Transferrin-Bound Iron Uptake

Alhough compelling evidence exists that the transferrin cycle is

important for iron acquisition by the erythron (Ponka and
Schulman, 1993; Ponka, 1997)), other tissues can import iron by
alternative mechanisms. Some patients and mutant mice that
have little or no circulating transferrin (Heilmeyer, 1966); (Goya et
al., 1972); (Bernstein, 1987); (Huggenvik et al., 1989). Despite
severe hypochromic, microcytic anemia, non-erythroid tissues are
grossly normal. While the red cells suffer from iron deficiency,
serum iron levels (iron not bound to transferrin) are elevated, and
excess iron is deposited in the liver. The iron-deprived bone
marrow likely signals the gut to increase absorption, exacerbating
tissue iron excess. Ponka and Schulman speculate that nonerythroid cells depend less on transferrin because their modest
iron needs can be met by turnover of endogenous ferritin and

heme iron. Red cells are more vulnerable because of greater iron
use to form hemoglobin (Ponka and Schulman, 1993; Ponka,
1997). The transferrin cycle could serve primarily to enhance iron
uptake by tissues with a great demand for the element.
Iron overload produces fully saturated transferrin and non-transferrin bound iron
circulating in a chelatable, low molecular weight form (Hershko et al., 1978);
(Hershko and Peto, 1978); (Craven et al., 1987); (Grootveld et al., 1989). This iron
is weakly complexed to albumin, citrate, amino acids and sugars, and behaves
differently from iron associated with transferrin. Non-hematopoietic tissues,
particularly the liver, endocrine organs, kidneys and heart preferentially take up
this iron.
Radiolabeled iron administered to mice with and without available transferrin
binding capacity has quite different patterns of distribution (Craven et al., 1987). In
normal animals, hematopoietic tissues are the prime sites of uptake. When free
transferrin sites are absent, however, most iron is deposited in the liver and
pancreas, indicating that these organs serve as iron reservoirs in the situation of
iron overload. Notably, this pattern of distribution is similar to that seen in
idiopathic hemochromatosis. These data support the idea that, while the transferrin
pathway is important for meeting the needs of the erythron, it is not essential for
iron uptake by all tissues.
Kaplan and coworkers have studied iron incorporation from FeNH 4 citrate
(Sturrock et al., 1990); (Kaplan et al., 1991). Intriguingly, they find that transferrinindependent uptake increases in direct proportion to the concentration of this
compound, similar to hepatic uptake of non-transferrin-bound iron in patients with
saturated transferrin. They speculate that this is a protective alternative pathway
that removes the toxic metal from the circulation. Other investigators have
described similar uptake in HepG2 cells, and shown that it is reversible by addition
of chelating compounds (Randell et al., 1994).
A non-transferrin iron uptake mechanism with different properties has been
described in K562 erythroleukemia cells (Inman and Wessling-Resnick, 1993). In
the absence of ferric transferrin, iron uptake into K562 cells is sensitive to
treatment with trypsin, suggesting that it requires a protein carrier. Higher ambient
iron concentrations do not increase cellular iron uptake. As discussed above, this
transport may be accomplished by the same machinery responsible for passage of
iron out of transferrin cycle endosomes into the cytoplasm (Pollack, 1992). These
two processes accomplish essentially the same task. The putative endosomal iron

transporter must be oriented to transport iron from an endocytosed extracellular

compartment into the cytoplasm. This transporter may exist on the cell surface
prior to receptor-mediated endocytosis, with the capacity to transport iron to a
modest extent. This activity is not restricted to erythroid cells. PHA-stimulated
human peripheral lymphocytes have a similar transferrin-independent iron uptake
mechanism (Hamazaki and Glass, 1992).

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http://sickle.bwh.harvard.edu/iron_transport.html

Iron metabolism
From bacteria to humans, many molecular structures and metabolic pathways involve
iron as an oxygen and/or electron carrier. However, despite its essential role for all living
beings, iron is toxic by inducing the formation of free radicals. As a consequence, the
human body has a fine regulation regarding the iron cycle and any unbalance can lead
to diseases such as hemochromatosis and thalassemia.

The iron cycle

The human body barely absorbs iron from the outside. In fact, its loss is very low due to
a constant recycling after the degradation of blood cells. The daily iron demand reaches
approximatively 20 mg, which contrasts greatly compared to a total pool of 3000 to 5000
mg in the human body.

Two cycles have been described for the iron metabolism: the inner and outer cycle. The
inner cycle consists of the exchange or iron between the red cells, plasma and different
tissues (liver, bone marrow and muscle) and is ensured by a soluble blood protein transferrine. Additionally, the outer cycle is only represented by the absorption of iron
from the intestins to the blood and its loss through tissue desquamation and skin
appendages. As a consequence, the plasmatic compartment plays a key role in iron
regulation and appears as the main crossroad between both cycles.

Iron demand and intestinal absorption

Despite the recommended daily allowance of iron is 20 mg, its absorbption only reaches
1 mg. This is correlated to the constant recycling of iron in the human body and the very
low loss (35% through skin desquamation and skin appendages and 65% through
instestinal secretion and desquamation. The iron requirements are covered by a healthy
and well-balanced diet.
Iron absorption is known to be absorbed in the duodenum (60%) and the jejunum (40%).
A low pH and a high rate of water directly influence its biodisponibility, thus being very
environmental dependant. However, the follwing rule is applicable in any
situation: ferrous iron is better absorbed than ferric iron.
Ferrous iron passes the enterocyte membrane by DMT1 (Divalent Metal Transporter 1).
The transporter's expression level can be increased, especially in case of anemia.
References:

Ganz, T., and Nemeth, E. (2011). Hepcidin and Disorders of Iron

Metabolism. Annual Review of Medicine 62, 347360.

Hentze, M.W., Muckenthaler, M.U., Galy, B., and Camaschella, C. (2010). Two to
Tango: Regulation of Mammalian Iron Metabolism.Cell 142, 2438. (link to the pdf)

Nicolas, G. (2004). Hepcidin, a candidate modifier of the hemochromatosis

phenotype in mice. Blood 103, 28412843. (link to the pdf)

Pantopoulos, K., Porwal, S.K., Tartakoff, A., and Devireddy, L.

(2012). Mechanisms of Mammalian Iron Homeostasis. Biochemistry 51, 57055724.

Viatte, L. (2006). Chronic hepcidin induction causes hyposideremia and alters the
pattern of cellular iron accumulation in hemochromatotic mice. Blood 107, 2952
2958. (link to the pdf)
http://2013.igem.org/Team:Evry/Project_metabolism

Iron Absorption
In general, the digestive system is set up to maximize absorption; there
is no regulation of the amounts of substances absorbed into the body. A
notable exception is iron, in which daily dietary absorption is regulated so
that it matches daily iron loss. The reason that absorption must be
carefully regulated is that the body does not possess a physiological
mechanism for regularly eliminating iron from the body. Iron is a

necessary component of various enzymes, but its major role is in oxygenbinding as a component of hemoglobin in red blood cells. Iron deficiency
leads toanemia, a decrease in the oxygen carrying capacity of blood.
However, too much iron in the body can be extremely toxic to tissues
because it promotes the formation of free radicals.
The majority of the body's iron is found in hemoglobin of developing and
mature red blood cells. Of the remaining iron, a significant portion is
stored in the liver, both in the hepatocytes, and in the Kupffer
cells (also known as reticuloendothelial cells), a type of macrophage
found in the liver. Kupffer cells play an important role in recycling body
iron. They ingest aged red blood cells, liberating iron for reuse by
breaking down hemoglobin.
The small amount of iron that is lost each day (about 1-2 mg) is matched
by dietary absorption of iron. The important players in the dietary
absorption of iron are diagrammed in the figure. (Note that this is a
simplified scheme; not all the details are included).
Iron is brought into the cell through an active transport process involving
the protein DMT-1(divalent metal transporter-1), which is expressed
on the apical surface of enterocytes in the initial part of the duodenum.
DMT-1 is not specific to iron, and can transport other metal ions such as
zinc, copper, cobalt, manganese, cadmium or lead. Enterocytes also
absorb heme iron through a mechanism that has not yet been
characterized.

Once inside the

enterocyte, there are
two fates for iron:

It may leave the

enterocyte and enter
the body via
the basolateral
transporter known
asferroportin.

It can be bound
to ferritin,
an intracellular
iron-binding
protein. For the most
part, iron bound to
ferritin in the
enterocyte will remain
there. This iron will be
lost from the body
when the enterocyte dies and is sloughed off from the tip of the villus.

Iron that enters the internal environment of the body from the basolateral
surface of the enterocyte is rapidly bound to transferrin, an ironbinding protein of the blood. Transferrin delivers iron to red blood cell
precursors, that take up iron bound to transferrin via receptor-mediated
endocytosis.
Normally, the capacity of transferrin to bind iron in the plasma greatly
exceeds the amount of circulating iron. The transferrin
saturation (percent of transferrin occupied by iron) is measured to
determine if an individual has an excessive load of iron in the body. The
normal transferrin saturation is in the range of 20-45%.

Iron absorption by the enterocyte is programmed to match the body's

needs. There are two major signals that affect iron absorption.
1. One signal reflects the need for iron due to erythropoiesis (red blood
cell generation). The hormone erythropoietin (produced by the kidneys)
stimulates red blood cell production, but it is NOT the signal regulating
iron absorption. Rather, once hematopoiesis is stimulated, another signal
is generated that promotes increased iron absorption.

2. A second signal depends upon the amount of iron in body stores.

Iron absorption is stimulated if the level in body stores is low.
These signals (and others) regulate iron absorption in the proximal
duodenum, where iron is absorbed. An important player in this
regulation is the recently discovered hormone hepcidin. Hepcidin is
produced by hepatocytes when iron stores are full. Inflammation can also
stimulate hepcidin production.

The figure shows the model for how hepcidin acts on duodenal
enterocytes to decrease the amount of iron absorbed into the body.
Experiments have shown that hepcidin binds to the basolateral iron
transporter ferroportin. This causes ferroportin to be internalized and
degraded. As a result, more iron remains within the enterocyte. This
stimulates ferritin synthesis, so that the iron that enters the enterocyte
gets bound to ferritin. This iron is lost from the body when the enterocyte
dies.

Hemochromatosis arises when there is an excess of iron in the body.

Excessive iron forms deposits in tissues, promoting free-radical formation
and damage to cells. Particular tissues that are affected are the joints,
liver, pancreas, heart and pituitary gland. The most prevalent form of
hereditary hemochromatosis is caused by a mutation in a gene known
as HFE. The mutation in HFE that causes hemochromatosis is quite

common in the Caucasian population, however, only some homozygotes

will develop hemochromatosis later in life (after middle age). Women with
mutations in HFE are to some degree protected from developing iron
overload because of regular blood loss through menstrual bleeding. A very
rare, severe juvenile form of hemochromatosis is due to a homozygous
deletion of the gene for hepcidin.
The exact function of the HFE protein is still being determined, but it is
thought that HFE functions in the process of sensing body iron levels and
regulating hepcidin secretion. Genetic experiments in mice have shown
that HFE function is required in hepatocytes to trigger normal levels of
hepcidin secretion in response to increased iron in the body. Individuals
with hereditary hemochromatosis have deficient secretion of hepcidin, and
so iron absorption by duodenal enterocytes continues even when body
iron stores are full.
Hemochromatosis is treated by reducing the load of iron in the body. This
is effectively accomplished by periodic phlebotomy (blood withdrawal).
Half a liter of blood contains approximately 200-250 mg of iron.

http://courses.washington.edu/conj/bess/iron/iron.htm