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Blood, 15 May 2002, Vol. 99, No. 10, pp. 3813-3822
RED CELLS
Erythroid differentiation and protoporphyrin IX
down-regulate frataxin expression in Friend cells: characterization of
frataxin expression compared to molecules involved in iron metabolism
and hemoglobinization
Erika M. Becker,
Judith M. Greer,
Prem Ponka, and
Des R. Richardson
From the Heart Research Institute, Iron Metabolism and
Chelation Group, Camperdown, Sydney, New South Wales,
Australia; the Department of Medicine, Royal Brisbane
Hospital, Herston, Brisbane, Queensland, Australia; and
The Lady Davis Institute for Medical Research, Montreal, Quebec,
Canada.
Friedreich ataxia (FA) is caused by
decreased frataxin expression that results in mitochondrial iron (Fe)
overload. However, the role of frataxin in mammalian Fe metabolism
remains unclear. In this investigation we examined the function of
frataxin in Fe metabolism by implementing a well-characterized model of
erythroid differentiation, namely, Friend cells induced using dimethyl
sulfoxide (DMSO). We have characterized the changes in frataxin
expression compared to molecules that play key roles in Fe metabolism
(the transferrin receptor [TfR] and the Fe transporter Nramp2) and hemoglobinization ( -globin). DMSO induction of hemoglobinization results in a marked decrease in frataxin gene (Frda)
expression and protein levels. To a lesser extent, Nramp2
messenger RNA (mRNA) levels were also decreased on erythroid
differentiation, whereas TfR and -globin
mRNA levels increased. Intracellular Fe depletion using
desferrioxamine or pyridoxal isonicotinoyl hydrazone, which chelate
cytoplasmic or cytoplasmic and mitochondrial Fe pools, respectively,
have no effect on frataxin expression. Furthermore, cytoplasmic or
mitochondrial Fe loading of induced Friend cells with ferric ammonium
citrate, or the heme synthesis inhibitor, succinylacetone,
respectively, also had no effect on frataxin expression. Although
frataxin has been suggested by others to be a mitochondrial ferritin,
the lack of effect of intracellular Fe levels on frataxin expression is
not consistent with an Fe storage role. Significantly, protoporphyrin
IX down-regulates frataxin protein levels, suggesting a regulatory role
of frataxin in Fe or heme metabolism. Because decreased frataxin
expression leads to mitochondrial Fe loading in FA, our data
suggest that reduced frataxin expression during erythroid
differentiation results in mitochondrial Fe sequestration for heme biosynthesis.
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