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. 2010 May 18;49(24):4945–4956. doi: 10.1021/bi1004798

Figure 3.

Figure 3

GLRX5 deficiency causes anemia but does not significantly affect non-erythroid tissues. In normal erythroblasts, ALAS2 and FECH in mitochondria contribute to heme synthesis, which is incorporated into hemoglobin (Hb). Erythroblasts are the only cells that express ALAS2, which contains a IRE in its 5′ UTR. All other cells express ALAS1, which is not regulated by the IRE−IRP system. Erythroblasts encode two forms of the ferroportin (FPN1) transcript, IRE-FPN1a and non-IRE-FPN1b. Both encode an identical FPN1 protein that functions as the iron exporter. Upon erythroid differentiation, both ALAS2 expression and FECH expression are upregulated, thus increasing the level of synthesis of heme and hemoglobin, while FPN1 expression is downregulated (65). In contrast, Fe−S cluster biogenesis is defective in GLRX5-deficient erythroblasts, iron accumulates in mitochondria, and associated iron deficiency in cytosol activates IRP proteins. The level of ALAS2 expression is decreased by IRP repression of its 5′ IRE. The level of FECH expression is also decreased, most likely because FECH does not acquire the Fe−S cluster it needs for stabilization (69). Together, heme synthesis and subsequent hemoglobinization are inhibited. Levels of expression of both FPN1 transcripts, including both FPN1a and FPN1b, are increased, perhaps in response to the stress caused by mitochondrial iron overload. Because FPN1b lacks the IRE, the expression of FPN1b evades the IRP repression and increases the level of expression of FPN1, which may exacerbate cytosolic iron deficiency. As a result, the GLRX5-deficient erythroblasts fail to produce enough heme for hemoglobinization upon differentiation. Although GLRX5-deficient non-erythroblasts also demonstrate iron overload in mitochondria and cytosolic iron deficiency, they express ALAS1, which does not have IRE and is not repressed by IRPs. Thus, heme synthesis is not significantly impaired in non-erythroid cell types. In addition, non-erythroblast cells express only FPN1a, which can be repressed by IRPs as cells develop cytosolic iron depletion.