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Blood, 15 December 2001, Vol. 98, No. 13, pp. 3823-3830
RED CELLS
Characterization of the iron transporter DMT1 (NRAMP2/DCT1)
in red blood cells of normal and anemic mk/mk
mice
François Canonne-Hergaux,
An-Sheng Zhang,
Prem Ponka, and
Philippe Gros
From the Departments of Biochemistry, Physiology, and
Medicine, McGill University, and the Lady Davis Institute for Medical
Research, Jewish General Hospital, Montreal, QC, Canada.
Divalent metal transporter 1 (DMT1) is the major
transferrin-independent iron uptake system at the apical pole of
intestinal cells, but it may also transport iron across the membrane of
acidified endosomes in peripheral tissues. Iron transport and
expression of the 2 isoforms of DMT1 was studied in erythroid cells
that consume large quantities of iron for biosynthesis of hemoglobin. In mk/mk mice that express a loss-of-function mutant
variant of DMT1, reticulocytes have a decreased cellular iron uptake
and iron incorporation into heme. Interestingly, iron release from transferrin inside the endosome is normal in mk/mk
reticulocytes, suggesting a subsequent defect in
Fe++ transport across the endosomal membrane.
Studies by immunoblotting using membrane fractions from peripheral
blood or spleen from normal mice where reticulocytosis was induced by
erythropoietin (EPO) or phenylhydrazine (PHZ) treatment suggest that
DMT1 is coexpressed with transferrin receptor (TfR) in erythroid cells. Coexpression of DMT1 and TfR in reticulocytes was also detected by
double immunofluorescence and confocal microscopy. Experiments with
isoform-specific anti-DMT1 antiserum strongly suggest that it is
the non-iron-response element containing isoform II of DMT1 that
is predominantly expressed by the erythroid cells. As opposed to
wild-type reticulocytes, mk/mk reticulocytes express little if any DMT1, despite robust expression of TfR, suggesting a possible effect of the mutation on stability and targeting of DMT1 isoform II in
these cells. Together, these results provide further evidence that DMT1
plays a central role in iron acquisition via the transferrin cycle in
erythroid cells.
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