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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 5

In cells from a GLRX5-deficient patient, aconitase activities are low and IRE-binding activities are increased.

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In cells from a GLRX5-deficient patient, aconitase activities are low an...
(A) Western blot analysis of patient lymphoblast cells. Lymphoblast 1 and 2 are WT controls. ABCB7 (ATP-binding cassette, sub-family B, member 7) is a control for mitochondrial proteins. α-Tubulin is loading control. (B) Western blot analysis of patient fibroblast cells. (C) In-gel aconitase activity assay with patient fibroblast and control cells. The top band is mitochondrial aconitase, whereas the bottom is cytosolic aconitase. (D) Band shift assay with patient fibroblast and control cells. IRP1 and tubulin Western blots verified equal loading. (E) Complex I activity assay and quantitation with patient fibroblast and control cells. Values for WT control cells are set at 100. Results represent the average of 3 repeats. For activity and quantitation, P = 0.00018 and 0.0032, respectively. (F) Quantitation of band intensity of FECH in A. Value for WT control is set at 100. Results represent the average of 3 repeats. P = 0.021. (G) Perls DAB nonheme iron staining in patient fibroblast cells. The bottom panel shows immunofluorescence staining of mitochondria using Tom20 (red) as a mitochondrial marker of WT and patient fibroblasts. Scale bars: 10 μm. (H) Quantitation of band intensity of IRP2 in B. Value for WT control is set at 100. Results represent the average of 3 repeats. P = 0.03. *P < 0.05; **P < 0.01.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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