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Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts
Hong Ye, … , Clara Camaschella, Tracey A. Rouault
Hong Ye, … , Clara Camaschella, Tracey A. Rouault
Published April 1, 2010
Citation Information: J Clin Invest. 2010;120(5):1749-1761. https://doi.org/10.1172/JCI40372.
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Research Article Hematology Article has an altmetric score of 3

Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts

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Abstract

Glutaredoxin 5 (GLRX5) deficiency has previously been identified as a cause of anemia in a zebrafish model and of sideroblastic anemia in a human patient. Here we report that GLRX5 is essential for iron-sulfur cluster biosynthesis and the maintenance of normal mitochondrial and cytosolic iron homeostasis in human cells. GLRX5, a mitochondrial protein that is highly expressed in erythroid cells, can homodimerize and assemble [2Fe-2S] in vitro. In GLRX5-deficient cells, [Fe-S] cluster biosynthesis was impaired, the iron-responsive element–binding (IRE-binding) activity of iron regulatory protein 1 (IRP1) was activated, and increased IRP2 levels, indicative of relative cytosolic iron depletion, were observed together with mitochondrial iron overload. Rescue of patient fibroblasts with the WT GLRX5 gene by transfection or viral transduction reversed a slow growth phenotype, reversed the mitochondrial iron overload, and increased aconitase activity. Decreased aminolevulinate δ, synthase 2 (ALAS2) levels attributable to IRP-mediated translational repression were observed in erythroid cells in which GLRX5 expression had been downregulated using siRNA along with marked reduction in ferrochelatase levels and increased ferroportin expression. Erythroblasts express both IRP-repressible ALAS2 and non-IRP–repressible ferroportin 1b. The unique combination of IRP targets likely accounts for the tissue-specific phenotype of human GLRX5 deficiency.

Authors

Hong Ye, Suh Young Jeong, Manik C. Ghosh, Gennadiy Kovtunovych, Laura Silvestri, Danilo Ortillo, Naoya Uchida, John Tisdale, Clara Camaschella, Tracey A. Rouault

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Figure 6

Rescue of GLRX5-deficient patient fibroblasts by transfection or transduction.

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Rescue of GLRX5-deficient patient fibroblasts by transfection or transdu...
(A) Growth curve and morphology of cells rescued by plasmid transfection. The top curve (red) indicates rescue cells transfected with pCMV-GLRX5, while the bottom line is the control that is transfected with pCMV only. P = 0.11, 0.0056, 0.0081, and 0.0077 for days 4, 8, 12, and 20, respectively. Morphology pictures are taken on day 8. (B) Immunofluorescence of GLRX5 and Tom20 in transfection-rescued cells. Rescue indicates cells that are transfected with pCMV-GLRX5, while control (Ctl) shows cells transfected with pCMV only. (C) Growth curve, GFP expression, and cell morphology of cells rescued by viral transduction. The top line (red) indicates rescue cells transduced with HIV1-GLRX5, while the bottom line is the control that is transduced with HIV1 only. P = 0.022, 0.28, 0.029, 0.042, and 0.0006 for days 0, 4, 8, 12, and 16, respectively. The HIV1 vector itself expresses GFP. Fluorescence pictures are taken on day 12. (D) Perls DAB nonheme iron staining. The top panels indicate patient cells transfected with either pCMV only (Ctl) or pCMV-GLRX5 (rescue), while the bottom panels show patient cells transduced with HIV1 only (Ctl) or HIV1-GLRX5 (rescue). (E) Aconitase activity assay. The cellular aconitase activity of patient cells is 14.2% of WT fibroblasts, but is restored to 63% of WT activity by GLRX5 viral transduction (rescue). P = 0.0052 and 0.0078 for rescue and WT, respectively. Scale bars: 50 μm (A and C); 10 μm (B and D). **P < 0.01.

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