Erythropoiesis and iron sulfur cluster biogenesis

Abstract

Erythropoiesis in animals is a synchronized process of erythroid cell differentiation that depends on successful acquisition of iron. Heme synthesis depends on iron through its dependence on iron sulfur (Fe-S) cluster biogenesis. Here, we review the relationship between Fe-S biogenesis and heme synthesis in erythropoiesis, with emphasis on the proteins, GLRX5, ABCB7, ISCA, and C1orf69. These Fe-S biosynthesis proteins are highly expressed in erythroid tissues, and deficiency of each of these proteins has been shown to cause anemia in zebrafish model. GLRX5 is involved in the production and ABCB7 in the export of an unknown factor that may function as a gauge of mitochondrial iron status, which may indirectly modulate activity of iron regulatory proteins (IRPs). ALAS2, the enzyme catalyzing the first step in heme synthesis, is translationally controlled by IRPs. GLRX5 may also provide Fe-S cofactor for ferrochelatase, the last enzyme in heme synthesis. ISCA and C1orf69 are thought to assemble Fe-S clusters for mitochondrial aconitase and for lipoate synthase, the enzyme producing lipoate for pyruvate dehydrogenase complex (PDC). PDC and aconitase are involved in the production of succinyl-CoA, a substrate for heme biosynthesis. Thus, many steps of heme synthesis depend on Fe-S cluster assembly.

Figure 1

The Fe-S biogenesis proteins, ISCA and C1orf69 (Iba57 homologue), may impact heme synthesis by affecting the production of succinyl-CoA, a substrate of heme synthesis. This proposed role is highly hypothetical and has not been shown in organisms that perform erythropoiesis. The ISCA- C1orf69 complex provides Fe-S clusters for lipoate synthase as suggested in yeast [63], which produces lipoate for a subunit of the pyruvate dehydrogenase complex (PDC). PDC converts pyruvate into acetyl-CoA, which enters the citric acid cycle to form citrate. The ISCA- C1orf69 complex provides the Fe-S cluster for mitochondrial aconitase, which converts citrate to isocitrate, which leads to synthesis of succinyl-CoA, a substrate for the first step in heme biosynthesis. All proteins are in the matrix. Other Fe-S proteins important in heme biosynthesis are ferrochelatase, which is unstable without its [2Fe-2S] cluster, and IRP1, which represses synthesis of ALAS2 when it lacks an Fe-S cluster. In the heme synthesis pathway, succinyl-CoA and glycine are condensed into 5-aminolevulinic acid (ALA). The subsequent six steps take place either in cytosol or in the intermembrane space of mitochondria. The last step is the insertion of a ferrous iron into protoporphyrin IX by ferrochelatase (FECH) to result in heme formation.