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Entry of iron into cells A new role for the transferrin receptor in modulating iron release from transferrin.

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Entrv of Iron into Cells: A New Role for
the Tiansferrin Receptor in Modulating Iron
Release from Transferrin
Philip Aisen, MD
The versatile chemistry of iron and the noxious reactions this essential metal may promote have compelled irondependent organisms to form specific iron-binding proteins to maintain iron in soluble, nontoxic, and accessible form
for cellular needs. A variety of pathways can be traversed by iron to gain access to cells, some available to all cells,
others restricted to specialized cells. Of these pathways, the most important and widely functioning is uptake of iron
from transferrin in a receptor-mediated process. By regulating expression of the transferrin receptor, iron-dependent
cells, including neurons, can be assured an adequate supply of the essential metal while guarding against toxic excess.
However, the transferrin receptor functions not only in capturing iron-bearing transferrin, but also in restraining
release of iron from transferrin at the cell surface, where iron-catalyzed lipid peroxidation is a threat, while facilitating
iron release in acidified endosomes to ensure safe and efficient delivery to the cell.
Aisen P. Entry of iron into cells: a new role for the transferrin receptor in modulating
iron release from transferrin. Ann Neurol 1992;32:S62-S68
The Aqueous Chemistry of Iron and the Need
for Iron-binding Proteins
The variety of uses to which iron has been put by
biological systems, the toxicity of iron, and the metabolic problems encountered by organisins dependent
on iron are all based on the simple aqueous chemistry
of this essential metal. In the anaerobic world, where
life began, management of iron in the ferrous state
posed no great difficulties for primitive species. Ferrous iron was abundant, soluble, tractable in its behavior inside or outside the cell, and adaptable to a variety
of metabolic processes. As living species increased in
complexity and number and learned to capture the
sun’s energy in photosynthesis, management of iron by
organisms that could not live without it presented new
problems for survival. The appearance of oxygen in
the atmosphere and the biological milieu meant that
the thermodynamically favored state of iron in the environment and in oxygenated cells was now ferric.
Consequences of this event were, and are, enormous.
Although ferrous iron is soluble to nearly 0.1 mol/
L even at physiological pH, ferric iron is soluble only
in strong acid. At neutral pH hydrolysis, formation of
insoluble iron hydroxides limits the concentration of
ferric iron to approximately
moYL 111, a concentration far too low to provide iron for even the most
meager of metabolic needs. Furthermore, when iron is
reduced from the ferric to the ferrous state, the inevita-
From the Department of Physiology and Biophysics, Albert Einstein
College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461.
ble propinquity of oxygen is likely to result in the
metal’s one-electron autooxidation back to the ferric
state, with simultaneous formation of oxyradicals. Organisms at all levels of complexity, living in an aerobic
world, have been compelled to evolve mechanisms and
molecules for transporting or storing iron in soluble
and bioavailable form while keeping it from dangerous
uncontrolled reactions with molecular dioxygen. In the
microbial universe, these requirements are largely satisfied by molecules termed siderophores, which are generally small and are used chiefly to mobilize iron from
the environment and transport it to the interiors of
cells. In the more complex domain of the vertebrates
(and perhaps invertebrates as well [2]), such transport
functions have been taken over by the transferrins.
These single-chain, two-sited proteins carry iron in the
circulation from intestinal mucosal or reticuloendothelial cells releasing the metal to cells storing iron or
dependent on iron for synthesis of iron-requiring enzymes and proteins. In virtually all species-whether
bacterial, fungal, plant, or animal-iron, once captured, is stored within the core of ferritin. This protein,
a hollow molecule of 24 subunits arranged in a nearly
spherical shell, can accommodate up to 4,500 atoms of
iron in its core, available on demand but otherwise
substantially protected from the oxidation-reduction
reactions hazardous to life. Ferritin may have more
than an iron storage role, however. Ferritin is normally
Address correspondence to Dr Aisen.
Pathways for Iron Entry into Cells
Cell Types
Maximum Rate of Uptake
Receptor-mediated endocytosis
of transferrin
Asialoglycoprotein receptormediated endocytosis of transferrin
Fluid phase endocytosis of transferrin
Adsorptive (nonsaturable) endocytosis of transferrin
Absorption of food iron
Uptake of ferritin (? receptormediated)
“Free” (nontransferrin) Fe(I1)
All iron-dependent cells
1 Fe/receptor/min (100,000
Uptake of heme-hemopexin,
atorndmin for a reticulocyte)
10,000 atoms/cell/min
All cells
Fetal hepatocytes
? (Function of transferrin concen-
Duodenal mucosal cells
Hepatocytes, T lymphocytes
R-E cells
? All cells
found in the circulation, and circulating ferritin is rapidly cleared and its iron recovered and stored by hepatocytes [ 3 ] . The possibility of an iron transport role for
ferritin is thereby suggested, perhaps acting to recover
for hepatocytes iron released from erythrophagocytosing Kupffer cells 147. To understand the diverse biological activities of transferrin and ferritin is to understand
iron metabolism.
Pathways for Entry of Iron into Cells
The evolution of specialized protein carriers and their
pathways for delivery of iron to cells fulfills several
functions. Iron is permitted to traverse the barrier imposed by the plasma membrane, whereas unsaturated
lipids of the membrane are protected from ironcatalyzed peroxidation. The cell is afforded a means to
regulate its traffic of iron to accommodate fluctuations
in demand, thereby guarding itself as effectively as possible from the dual hazard of iron deficiency and iron
surfeit. Except when the stress of iron shortage or surplus is extreme or prolonged, the normal mechanisms
in cellular uptake of iron maintain cells in optimal iron
balance. The Table offers a summary of known routes,
normal, pathological, and experimental, for iron entry
into cells.
Iron Uptake from Transfeuin
The transfeuin receptor:
By far, the most important means taken by virtually all
cells, including mammalian cortical neurons 15, 61, to
satisfy their need for iron is receptor-dependent uptake
from transferrin. In the last decade, the major features
of this route have been delineated 17, 81. The initial
event is the capture of iron-laden transferrin by the
<500,000 atoms/cell/min
2,000,000 atoms/cell/min in isolated hepatocytes
40,000,000 atoms/cell/min
? 100,000 to 10,000,000 atoms/
E3 11
E62, 631
transferrin receptor of the cell surface. At the p H of
the cell surface (7.4), the transferrin receptor effectively recognizes only iron-bearing transferrin, because
the affinity of receptor for apotransferrin is nearly two
orders of magnitude less than its affinity for ironbearing transferrin 191. Thus, in times of iron deficiency when most circulating transferrin molecules are
devoid of iron, what iron-bearing transferrin molecules
there are will encounter no effective competition for
binding to receptor. Also worth noting is the finding
that singly occupied (monoferric) transferrin has an affinity for receptor intermediate between that of apotransferrin and diferric transferrin 197; when available,
the doubly occupied protein will still be preferentially
seized by the receptor. Again, the effect is to maximize
efficiency of the receptor-dependent pathway in cellular uptake of iron from transferrin. Furthermore, in
times of iron surfeit, genetic regulatory mechanisms
suppress the expression of transferrin receptor [ 10127, thereby preventing the cell from taking iron it
does not need. The transferrin receptor-dependent
pathway thus functions as both grapple and gatekeeper
in controlling the entry of iron into cells.
Binding of iron-transferrin to its receptor is then
followed by internalization of the receptor-transferrin
complex to a membrane-bound, clathrin-coated, proton-pumping endosome, where a p H near 5.6 is
achieved [7]. Such acidification weakens the ironprotein bonds in transferrin to facilitate release of the
metal to the cell, and agents that interfere with endosomal acidification impede release of iron from transferrin to the cell 1131. Lowering the p H alone may not
be sufficient to enable release of iron from transferrin;
as will be seen, the receptor may have a central role in
Aisen: Transferrin Receptor in Iron Release from Transferrin
iron to hepatocytes is therefore dubious, but it may
account in small part for increased iron uptake by the
liver in alcoholism, a condition in which the relative
concentration of desialylated transferrin is increased
Fig I . Uptake of iron by cells via receptor-mediated endocytosis
of transfewin. In most cells, the entire cycle may take no more
than 2 to 3 minutes. Both transfewin and its receptor are conserved during the cycle. (From {bl). Used with permission.)
facilitating iron release. Despite loss of its iron, transferrin remains bound to receptor, which, at the low
pH of the endosome, binds apotransferrin even more
strongly than iron-transferrin 1141. Finally, the complex of receptor- and iron-depleted transferrin returns
to the cell surface, where, at pH 7.4, the proteins dissociate so each is freed for another cycle of iron transport. Both transferrin and its receptor are glycoproteins; the carbohydrate chains of each are required for
normal function 115, 161.
The three distinctive features of the transferrin-tocell cycle in iron metabolism (Fig 1) are (1) throughout
its journey through the cell, transferrin remains complexed to its receptor; (2) at extracellular p H (7.4), the
transferrin receptor preferentially binds to iron-bearing
transferrin, but at endosomal p H (5.6), it favors apotransferrin; and ( 3 ) the entire cycle may be completed
within 2 or 3 minutes {171. Possible physiological implications and experimental study of these features will
be considered.
The asialoglycoprotein receptor: Normal hepatocytes
express an asialoglycoprotein receptor capable of clearing desialylated glycoproteins from the circulation
118). Possibly, this receptor functions jointly with the
transferrin receptor in the hepatocyte's engagement
and internalization of transferrin 1191. Under physiological conditions, the maximum uptake of transferrinborne iron via the asialoglycoprotein receptor-mediated pathway is probably no more than lo4 atoms
Fe/hepatocyte/min C20). The physiological importance
of the asialoglycoprotein receptor in the delivery of
Although hemoglobinsynthesizing immature erythroid cells (often taken as
models of cells with substantial iron requirements)
depend essentially exclusively on transferrin receptors
to obtain iron from transferrin, other cells needing iron
may circumvent the transferrin receptor. Perhaps the
most complex, most studied, and least understood of
such cells is the hepatocyte.
The existence of transferrin receptors on the plasma
membrane of the hepatocyte and the participation of
these receptors in the acquisition of iron from transferrin by the cells is now generally accepted 122-241.
Whether important receptor-independent routes for
transferrin to deliver iron to the hepatocyte also exist
is much less clear. Binding and uptake of iron by primary cultures of these specialized cells seem to entail
nonspecific or nonsaturable cellular mechanisms or adsorptive endocytosis 124, 251, in addition to receptordependent processes. In cultured cells, these lowaffinity, nonsaturable pathways may provide more iron
for hepatocytes than the high-affinity, receptor-dependent routes used by most other cells. Such nonspecific uptake, however, may be much less important
in vivo, because nonmammalian transferrins, which
have low affinity for the rat transferrin receptor but
should function in receptor-independent processes like
homologous transferrin, are poor providers of iron for
liver 1261.
Iron Uptake from Ferritin
Within 24 hours of its intravenous injection, more than
85% of rat ferritin is recovered in the livers of recipient rats, with little or no appearance of the protein or
its iron in other tissues 131. The inference from this
fundamental observation is that hepatocytes express a
receptor capable of recognizing, binding, and internalizing ferritin; ferritin may therefore have a role in
iron transport as well as iron storage. Binding and uptake of ferritin by cultured rat hepatocytes conform to
what is expected of a receptor-mediated process 1271,
and isolation of a specific ferritin receptor from liver
has been reported [28, 291. Because the ferritin molecule may contain up to 4,500 solubilized iron atoms (as
polynuclear FeOOH), hepatocytes may acquire much
more iron from ferritin than from transferrin, even
though the cycle time for ferritin is substantially slower
than that for transferrin 127). A variety of other cells
have also been reported to express ferritin receptors
1301, but the importance of imported ferritin as a
source of iron for cells is not yet clear.
S64 Annals of Neurology Supplement to Volume 32, 1992
Specialized Puthways for Iron Uptake
Cells with specialized functions in the metabolism of
iron have evolved correspondingly specialized pathways for taking up and discharging iron. In general,
much less is understood of these pathways than is
known of uptake from transferrin.
acquired, and in a shorter time, by erythrophagocytosing macrophages than by any other cell in the vertebrate organism. Each ingested red cell presents a burden of lo9 iron atoms to the ingesting cell, and each
ingesting cell may rapidly engulf 10 to 15 or more red
cells [31, 32). Such unrestrained phagocytosis has its
hazards, however, because the likelihood of a macrophage surviving the gluttony is small E32). Whether
the killing of macrophages by too exuberant erythrophagocytosis is a consequence of acute iron overload
and toxicity or is due to other mechanisms is not yet
known. Erythrophagocytosing macrophages may interiorize more than 10 red cells in 30 minutes, but some
40 hours are required for surviving cells to recover
fully from the stress of such vigorous erythrophagocytosis 13 1). In vivo, repeated or sustained hemorrhage
will result in loading of macrophages with stainable
iron, presumably in the form of ferritin at first and,
with time, as hemosiderin, which is believed to be an
insoluble derivative of ferritin capable of promoting
noxious reactions within the cell [33).
More than 50% of the iron taken up by erythrophagocytosing cells may be eliminated as ferritin [341,
but the secretory mechanisms for elimination of ferritin are obscure. A substantial fraction of the iron is
also released in a form available for rapid binding by
transferrin, but, again, the chemical nature of this iron
is not known.
Whether glial cells manage the processing of ingested red cells and hemoglobin as do peripheral reticuloendothelial cells is also unclear. The usual assumption, based on morphological findings, is that microglia
and blood-derived monocytes manage the cleanup
after central nervous system (CNS) bleeding. Because
of the frequency and importance of CNS hemorrhage
in human disease, this question is of substantial concern and it deserves more investigation than it has received.
cells are specialized for absorption of food iron. Assuming there are 10” absorbing cells in the duodenum,
a figure derived from the known cross-sectional area
of a mucosal cell and the estimated absorbing area of
the duodenum, the maximal rate of iron transport
across the duodenal mucosal cell is approximately 5 x
lo5 atomdmin. Transferrin has been suggested to be
involved in uptake of iron by mucosal cells {35), but
this view has not generally been accepted and is inconsistent with the distribution of transferrin receptors on
intestinal mucosal cells as well as with the absorption
of iron in atransferrinemic mice [36, 37). Again, the
molecular mechanisms underlying iron absorption,
transport, and discharge to the circulation, and the regulation of these events, are poorly understood. Several
models have been proposed 138-401, but none has yet
achieved consensus status.
Perhaps because of its
continuous need for iron, hepatocytes can exploit a
number of mechanisms in satisfying their demands,
which include uptake of heme-hemopexin, methemalbumin, and hemoglobin-haptoglobin. None appear to
be very important in contributing to the iron economy
of the liver.
Uptuke of Nonprotein-bound Iron
In acute or severe chronic iron overload, iron may appear in the circulation in “free” form (i.e., in the form
of low molecular weight complexes rather than carried
by specific iron-binding proteins). Such low molecular
weight iron, the extracellular analogue of the “labile
iron pool” within cells [41), is apt to be more reactive
chemically than iron sequestered by transferrin or ferritin and therefore a greater hazard to cells. Citrate, a
biologically ubiquitous chelator of iron, has been identified as a carrier of nontransferrin circulating iron 1421,
but in all likelihood other biological complexing agents
may also function as vehicles of nonprotein iron in or
out of cells. When presented to cultured cells in the
ferrous state, iron appears capable of spontaneously
penetrating the cell membrane and participating in the
usual metabolic reactions of the recipient cell, including synthesis of heme 143-451. At the high oxygen
tensions of circulating blood, however, the stable form
of iron in most complexes is Fe(III), so it is improbable
that significant concentrations of Fe(11) can be achieved
in the circulation.
Cells in culture may be loaded with iron offered as
simple complexes, such as ferric ammonium citrate
C46) or ferric nitrilotriacetate [47). Such iron may be
incorporated into ferritin but is also capable of exerting
toxic effects. In one study, iron taken up from its complex with nitrilotriacetate by a hepatoma-derived cell
line was largely associated with cell membranes C471.
The pathophysiological implications of cellular studies
with simple iron complexes are therefore somewhat
uncertain. Hazards of circulating low molecular weight
complexes of iron are most clearly evident in acute
iron poisoning, during which the iron concentration of
blood may exceed the iron-binding capacity of transferrin by factors of 10 or more {48). In such circumstances, the circulatory collapse and the liver and CNS
damage characteristic of iron poisoning are proba-
Aisen: Transferrin Receptor in Iron Release from Transferrin S65
bly attributable to the rush of nontransferrin-bound
iron into vulnerable cells. Much more insidious is the
accumulation of tissue iron in disorders of chronic
iron overload, such as hemochromatosis and the
transfusion-dependent hemolytic anemias. In these
conditions, nontransferrin-bound iron may be found in
the circulation 1491, although at much lower levels than
seen in acute iron poisoning.
An enigma is presented by disorders of focal iron
accumulation not caused by hemorrhage and in which
no generalized defect in iron metabolism and no abnormality in serum iron transport is known. Hallevorden-Spatz disease, characterized by progressive accumulation of iron in the globus pallidus 1501; Fahr's
syndrome of striopallidodentate calcinosis 1511; and
possibly Parkinson's disease {521 are disorders of localized iron accumulation in the CNS without evidence
of systemic disturbance in iron metabolism. It is usually
difficult to be confident that the iron accumulation represents a primary event rather than a consequence of
hemorrhage or localized tissue injury remote in time.
No mechanism is now understood and accepted to account for focal iron overload.
New Roles for the Transferrin Receptor i n the
Delivery of Iron to Cells
Cell surface receptors for specific molecules usually
function to recognize, capture, and convey their ligands
to appropriate destinations in the interior of the cell
or to initiate a sequence of transducing signals when
activated by their ligands. Almost with discovery of the
function of transferrin in delivering iron to cells came
the recognition that such delivery depended on the
integrity of specific cell-surface receptors for transferrin C53]. Recently, a new role for the transferrin
receptor beyond that of recognition and transport of
transferrin to the interior of the cell has been proposed.
As discussed earlier, transferrin is accompanied by
its receptor throughout its 2- to 3-minute sojourn with
cells. This fact suggests that the receptor may function
to modulate release of iron from transferrin to the cell.
Experimental evidence now supports this hypothesis,
thereby helping to explain the rapidity with which cellular release of iron from transferrin is accomplished.
Experimental Studies
To explore the consequences of receptor binding on
release of iron from transferrin, pure preparations
of detergent-solubilized transferrin receptor were obtained from normal human placentas I541. Complexes
of purified receptor and transferrin were chromatographically isolated from incubation mixtures of receptor and 59Fe-labeled diferric transferrin. As expected
of a protein comprised of two identical subunits, each
receptor molecule bound two molecules of transferrin.
tW 80
Time (min)
Fig 2. Comparative study of iron release from transfewin and
the complex of transferrin and its receptor t o .50 mmoilL pyrophosphate (pH 7.41. Closed circles indicate release from transfewin bound to receptor; open circles indicate release from free
transferrin. (Data from 1541.1
Release of iron from the complex of transferrin and its
receptor to inorganic pyrophosphate, the iron-binding
moiety of adenosine triphosphate [5 51, was studied
and compared with release of iron from free transferrin
under otherwise identical conditions.
first encounters its receptor at the cell surface, where
the p H is 7.4. Accordingly, the release of iron from
transferrin to pyrophosphate was studied in a buffer
of 0.05 moVL HEPES/O.l moVL NaCVO.01 moYL
CHAPS detergent (pH, 7.4). At this pH, where the
binding of iron by free transferrin has an effective stability constant at ambient carbon dioxide tension near
5 x lo2' M-' 1561, measurable release was obtained
only with a 50 mmoVL concentration of pyrophosphate, an unphysiologically high value. Even so, the
half-time for release is approximately 8 minutes (Fig
2), much longer than the time taken by the cell to
release iron from transferrin. When bound to its receptor, however, the rate of release is further slowed by
a factor of nearly 10 (see Fig 2). Could this slowing
have a biological role?
Phosphate groups abound in cell membrane phospholipids, which appear to be intimately involved in
the interaction of transferrin with cells 1571. The affinity of phosphate for iron has long been known and is
exploited by the egg yolk protein phosvitin for binding
S66 Annals of Neurology Supplement to Volume 32, 1992
gent-solubilhed receptor mimics receptor in the endosomal membrane, we suggest that the transferrintransferrin receptor interaction accounts, at least in
large part, for rapid iron removal in the endosome.
The complex of transferrin and its receptor is poised
to deliver iron on acidification of the endosome but
tenaciously retains iron before acidification, thus assuring safe and efficient delivery of iron to cells.
.+- 80
2 50
Preparation of this manuscript, and the research reported in it, were
supported in part by grant DKl5056 from the National Institutes
of Health, US Public Health Service.
c 30
Time (min)
Fig 3 . Comparative study of iron release from transfewin and
the complex of transferrin and its receptor to 1 mmollL pyrophosphate (pH 5.6). Closed circles indicate release from transfewin bound to receptor; open circles indicate release fmm free
transferrin.(Data from {54).)
and transport of iron in the chick embryo [58]. Untargeted release of even trace amounts of iron from transferrin to phosphate groups of the cell membrane might
be sufficient to promote lipid peroxidation in the membrane [57}. Retardation of iron release from transferrin
by the transferrin receptor would insure against such a
potentially disastrous event.
Release of iron at the cell surface is avoided, but release
of iron within the acidified endosome is essential for
transferrin to fulfill its role in the delivery of iron to
cells. The effect of the transferrin receptor on iron
release from transferrin was therefore studied at the
pH of the acidified endosome (5.6). At this lower pH,
instead of retarding release, the receptor accelerates
freeing of iron from transferrin (Fig 3). Indeed, at endosomal pH, a concentration of pyrophosphate in the
physiological range (1.0 mmoUL) now effects release
of 50% of the iron from diferric transferrin in less than
3 minutes, a time close to that taken by the living cell.
In contrast, free transferrin under similar conditions
has a half-time for release of more than 15 minutes,
far longer than the time required for iron release in
the cell. Also, in this time, only one site of free diferric
transferrin releases its iron, whereas both sites of receptor-bound diferric transferrin relinquish their iron.
From these observations, and assuming that deter-
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S68 Annals of Neurology Supplement to Volume 32, 1992
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entry, release, iron, transferred, role, modulation, receptov, new, cells
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