The disruption of protein-protein interaction in mitochondria results in sideroblastic anemia.

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We have identified that beta-subunit of ATP specific succinyl CoA synthase (SCS-betaA) associate with the erythroid specific 5-aminolevulinate synthase (ALAS-E), which is the rate limiting enzyme of heme biosynthetic pathway in erythroid cells. This protein interaction occurred in mitochondria should be important for effective heme production, because succinyl CoA is one of the substrates of ALAS-E for producing aminolevulinic acid. In fact, we have identified that the mutation of the ALAS-E gene, which was identified in the pedigree of pyridoxine refractory X-linked sideroblastic anemia, disrupt this interaction with SCS-betaA, resulting sideroblastic anemia. Since the reduced enzymatic activity of ALAS-E in erythroblast results in X-linked sideroblastic anemia, we have speculated that the disruption of the interaction between ALAS-E and SCS-bataA cause sideroblastic anemia. Thus, we have tried to reduce the expression of SCS-betaA using siRNA technique in erythroid cells. As a result, we found that reduced level of mRNA of SCS-betaA in erythroid cells interfere the erythroid differentiation, which was judged by hemoglobin staining. Our results indicate that the disruption of the association between ALAS-E and SCS-betaA affect the effective heme production in erythroid cells, and it may cause sideroblastic anemia.