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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1749-1761
Number of pages13
JournalJournal of Clinical Investigation
Volume120
Issue number5
DOIs
Publication statusPublished - May 3 2010

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Sideroblastic Anemia
Glutaredoxins
Erythroblasts
Heme
Iron
Erythroid Cells
Iron Overload
Iron Regulatory Protein 1
Ferrochelatase
Aconitate Hydratase
Phenotype
Mitochondrial Proteins
Zebrafish
Sulfur
Small Interfering RNA
Transfection
Anemia
Homeostasis
Down-Regulation
Fibroblasts

ASJC Scopus subject areas

  • Medicine(all)

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Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts. / Ye, Hong; Jeong, Suh Young; Ghosh, Manik C.; Kovtunovych, Gennadiy; Silvestri, Laura; Ortillo, Danilo; Uchida, Naoya; Tisdale, John; Camaschella, Clara; Rouault, Tracey A.

In: Journal of Clinical Investigation, Vol. 120, No. 5, 03.05.2010, p. 1749-1761.

Research output: Contribution to journalArticle

Ye, Hong ; Jeong, Suh Young ; Ghosh, Manik C. ; Kovtunovych, Gennadiy ; Silvestri, Laura ; Ortillo, Danilo ; Uchida, Naoya ; Tisdale, John ; Camaschella, Clara ; Rouault, Tracey A. / Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 5. pp. 1749-1761.
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