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

我们已经鉴定了ATP特异性琥珀酰CoA合酶（SCS-β A）的β亚基与红系细胞特异性5-氨基乙酰丙酸合酶（ALAS-E）结合，ALAS-E是红系细胞血红素生物合成途径的限速酶。这种发生在线粒体中的蛋白质相互作用对于有效的血红素生产应该是重要的，因为琥珀酰CoA是ALAS-E产生氨基乙酰丙酸的底物之一。事实上，我们已经确定，ALAS-E基因的突变，这是在吡哆醇难治性X-连锁铁粒幼细胞性贫血的家系中发现的，破坏了与SCS-β A的相互作用，导致铁粒幼细胞性贫血。由于ALAS-E在成红细胞中的酶活性降低导致X-连锁铁粒幼细胞性贫血，我们推测ALAS-E和SCS-bataA之间的相互作用的破坏导致铁粒幼细胞性贫血。因此，我们尝试使用siRNA技术降低红系细胞中SCS-β A的表达。结果，我们发现红系细胞中SCS-β A mRNA水平的降低干扰了红系分化，这通过血红蛋白染色来判断。我们的研究结果表明，ALAS-E和SCS-β A之间的关联的破坏影响了红系细胞中血红素的有效产生，并且可能导致铁粒幼细胞性贫血。

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.