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.
