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

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

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 9

A working model to describe how GLRX5 deficiency in erythroblasts impairs heme biosynthesis, depletes cytosolic iron, and potentially causes SA.

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A working model to describe how GLRX5 deficiency in erythroblasts impair...
GLRX5 contributes to [Fe-S] cluster biogenesis and mitochondrial iron homeostasis in every tissue. Like many other [Fe-S] synthetic proteins, the deficiency of GLRX5 leads to mitochondrial iron accumulation. As reported in this study, GLRX5 has an additional role in erythropoiesis. In normal erythroblasts, ALAS2 and FECH are upregulated to generate large amounts of heme during erythropoiesis or DMSO-induced differentiation. GLRX5 is required to maintain mitochondrial iron homeostasis, which then allows normal ALAS2 protein translation and supports formation of FECH holo-protein. In GLRX5-deficient erythroblasts, GLRX5 deficiency impairs mitochondrial [Fe-S] biogenesis, induces relative cytosolic iron depletion, and activates IRE-binding activity of both IRP1 and IRP2. ALAS2 is repressed by IRPs; FECH is degraded in the absence of [Fe-S] clusters, and heme biosynthesis is accordingly impaired. In addition, the increased ferroportin (FPN1) generated from a non-IRE containing transcript (FPN1b) may deplete cytosolic iron in the GLRX5-deficient erythroblasts. GLRX5-deficient nonerythroblasts do not express ALAS2 and do not need much FECH to synthesize heme. They also express FPN1a, a transcript that contains an IRE, and is subject to translation repression from activation of IRE-binding activity. Therefore, the disturbance to heme synthesis is minimal, and nonhematopoietic tissues do not demonstrate significant phenotypes.