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Blood, 15 April 2007, Vol. 109, No. 8, pp. 3552-3559.
Prepublished online as a Blood First Edition Paper on December 27, 2006; DOI 10.1182/blood-2006-08-041632.
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RED CELLS
RNA silencing of the mitochondrial ABCB7 transporter in HeLa cells causes an iron-deficient phenotype with mitochondrial iron overload
Patrizia Cavadini1,
Giorgio Biasiotto1,
Maura Poli1,
Sonia Levi2,
Rosanna Verardi3,
Isabella Zanella1,
Manuela Derosas1,
Rosaria Ingrassia1,
Marcella Corrado1, and
Paolo Arosio1
1 Dipartimento Materno Infantile e Tecnologie Biomediche, University of Brescia, Spedali Civili, Brescia, Italy;
2 Unit of Proteomics of Iron Metabolism, Vita e Salute San Raffaele University, Milan, Italy;
3 Section of Immunohematology and Transfusional Medicine, Spedali Civili, Brescia, Italy
X-linked sideroblastic anemia with ataxia (XLSA/A) is caused by defects of the transporter ABCB7 and is characterized by mitochondrial iron deposition and excess of protoporphyrin in erythroid cells. We describe ABCB7 silencing in HeLa cells by performing sequential transfections with siRNAs. The phenotype of the ABCB7-deficient cells was characterized by a strong reduction in proliferation rate that was not rescued by iron supplementation, by evident signs of iron deficiency, and by a large approximately 6-fold increase of iron accumulation in the mitochondria that was poorly available to mitochondrial ferritin. The cells showed an increase of protoporphyrin IX, a higher sensitivity to H2O2 toxicity, and a reduced activity of mitochondrial superoxide dismutase 2 (SOD2), while the activity of mitochondrial enzymes, such as citrate synthase or succinate dehydrogenase, and ATP content were not decreased. In contrast, aconitase activity, particularly that of the cytosolic, IRP1 form, was reduced. The results support the hypothesis that ABCB7 is involved in the transfer of iron from mitochondria to cytosol, and in the maturation of cytosolic Fe/S enzymes. In addition, the results indicate that anemia in XLSA/A is caused by the accumulation of iron in a form that is not readily usable for heme synthesis.
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