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2159
CORRESPONDENCE
MECHANISM OF IRON UPTAKE
To the Editor:
In the June 1, 1991 issue of Blood, Cochran et all found that the
primary pathway for initial uptake of AI-transferrin and Fetransferrin by human fetal red cells (obtained from placentas) was
through a high-affinity saturable receptor that did not distinguish
between the two metallo-transferrins; that a process that followed
initial uptake did distinguish between the two metallo-transferrins;
and that as much as 20% of the uptake of metallo-transferrin, at
physiologic concentrations of protein, was by way of a low-affinity,
nonsaturable receptor.
The differential handling of Al-transferrin and Fe-transferrin
after they have been endocytosed, as discussed by the Cochran et
all may be due to the differential release of Al and Fe from the
endocytosed metallo-transferrins or differential transport of the
two metals after their release. There is another possibility. Recent
experiments have shown that mitochondria have receptors for
ironzs3;AI and Fe might compete for binding to these receptors.
The postulate of a low-affinity nonsaturable receptor seems at
odds with the usual characteristics of a receptor, of which saturability is one. The low-affinity, nonsaturable uptake may perhaps be
more easily explained by the receptor-independent endocytosis
that is characteristic of fetal erythrocytes.'
SIMEON POLLACK
Albert Einstein College of Medicine
Bronx, Ny
REFERENCES
1. Cochran M, Chawtur V, Jones ME, Marshall E A Iron uptake
by human reticulocytes at physiologic and subphysiologicconcentrations of iron transferrin: The effect of interaction with aluminum
transferrin. Blood 77:2347, 1991
2. Weaver J, Zhan H, Pollack S: Mitochondria have Fe(II1)
receptors. Biochem J 265415,1990
3. Weaver J, Pollack S: Two types of receptors for iron on
mitochondria. Biochem J 271:463,1990
4. Colin FC, Schrier S L Spontaneous endocytosis in human
neonatal and adult red blood cells: Comparison to drug-induced
endocytosis and to receptor-mediated endocytosis. Am J Hematol
37:34,1991
RESPONSE
We thank Dr Pollack for his comments and for drawing our
attention to these recent publications. He refers to our finding that,
when we compared the handling of diferric transferrin (FeTr) and
aluminum transferrin (AlTr) by reticulocytes, after initial uptake,
the cells appeared to distinguish between the two forms of
metallo-transferrin. He raises the question as to whether the Al
and Fe might compete at the mitochondrial receptor, which is an
interesting possibility, especially as AI has a high affinity for ATP'
and it is the Fe-ATP receptor to which he refers. Competition at
this point might explain the inhibition of heme synthesis that has
been shown to result from exposure to AI? Our data did not
examine in any way the internal fate of the Fe, so we are unable to
comment on the likelihood of Al and Fe competing at this site.
However, as far as AlTr and FeTr are concerned, our data showed
that, once the indistinguishable surface binding of AlTr or FeTr to
the classical high-affinity receptor had been accounted for, there
was no competition for 59Feuptake from excess AlTr. On the other
hand, with regard solely to Fe accumulation, we found that an
internal rate-limiting step existed. We tentatively suggested that
this was at the point of binding to a transport protein in the vesicle
membrane because with our procedure, which simply measured
'Te accumulation, a rate-limiting step later in the pathway would
not have been recognized; the iron in the cell, in whatever form,
would still have been counted. Thus, the appealing idea that Al and
Fe, bound to ATP, might compete for binding to the mitochondrion receptor remains speculative.
Regarding our postulate of a low-affinity, high-capacity receptor,
we feel confident that a molecular structure with these characteristics must exist in the vicinity of the transferrin receptor clusters.
Putting aside the semantic question of the definition of a receptor,
such an arrangement would make good sense. If the purpose of the
endocytic vesicle is to expose the metallo-transferrin to a marked
change in the chemical environment, the inclusion of extra metallotransferrin would provide extra metal at minimal extra cost to the
cell. We would propose that a loosely arranged surface structure in
the base of the crypt would form a labyrinth into which the
metallo-transferrin could diffuse. We considered the possibility
that our concentration-dependent uptake was simply a reflection of
random endocytosis. We disliked this idea for two reasons. Firstly,
simple pinocytosis would be an extremely inefficient way of
capturing metallo-transferrin. Secondly, Trinder et al' tested this
possibility in hepatocytes using a soluble labeled nonabsorbable
marker and found that the volume of the vesicles and their rate of
formation could not account for the observed uptake by the
diffusion-dependent process.
M. COCHRAN
M.E. JONES
Departments of Medicine and Anatomy
Flinders University
Bedford Park
South Australia
REFERENCES
1. Karlik SJ, Elgarvish GA, Eichhom G L Multinuclear NMR
3. Trinder D, Morgan EH, Baker E The effect of an antibody to
studies on Al"' complexes of ATP and related compounds. J Am
the rat transferrin receptor and of rat serum albumin on the uptake
Chem SOC105:602,1983
of diferric transferrin by rat hepatocytes. Biochem Biophys Acta
2. Abreo K, Glass J, Sella M: Aluminum inhibits hemoglobin
943:440,1988
synthesis but enhances iron uptake in Friend erythroleukemic cells.
Kidney Int 37:677,1990
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
1991 78: 2159
Mechanism of iron uptake [letter; comment]
S Pollack
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