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

线粒体中蛋白质-蛋白质相互作用的破坏导致铁粒幼细胞贫血。

基本信息

批准号：
15590266
负责人：
FURUYAMA Kazumichi
金额：
$ 2.24万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590266/
关键词：
aminolevulinate synthase succinyl CoA synthethase hereditary sideroblastic anemia RNA interference

项目摘要

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.

我们发现ATP特异性琥珀酰辅酶a合成酶（scs - β - aa）的β亚基与红系特异性5-氨基乙酰化合成酶（ALAS-E）相关，后者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产生应该是重要的，因为琥珀酰辅酶a是ala - e产生氨基乙酰丙酸的底物之一。事实上，我们已经发现，在吡哆醇难愈性x连锁铁母细胞性贫血谱系中发现的ALAS-E基因突变破坏了与scs - β - aa的相互作用，导致铁母细胞性贫血。由于红细胞中ALAS-E酶活性的降低导致x连锁的铁母细胞性贫血，我们推测ALAS-E和SCS-bataA之间相互作用的破坏导致了铁母细胞性贫血。因此，我们尝试使用siRNA技术在红细胞中降低scs - β - aa的表达。通过血红蛋白染色，我们发现红细胞中scs - β aa mRNA水平的降低干扰了红细胞的分化。我们的研究结果表明，破坏ala - e和scs - β - aa之间的联系会影响红细胞有效的血红素产生，并可能导致铁母细胞性贫血。