Truncated product of the bifunctional DLST gene involved in biogenesis of the respiratory chain
Truncated product of the bifunctional DLST gene involved in biogenesis of the respiratory chain
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DOI：
10.1093/emboj/cdg299
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发表时间：
2003-06-16
期刊：
影响因子：
11.4
通讯作者：
Ohta, S
中科院分区：
文献类型：
--
作者：
Kanamori, T;Nishimaki, K;Ohta, S
二氢硫辛酰胺琥珀酰转移酶（DLST）是克雷布斯循环的α-酮戊二酸脱氢酶复合物的亚基酶。在研究DLST基因型如何有助于阿尔茨海默病（AD）的发病机制时，我们发现了一种新的mRNA，该mRNA从DLST基因的内含子7开始转录。AD患者脑组织中新基因mRNA水平显著低于对照组。截短的基因产物（命名为MIRTD）定位于线粒体的膜间隙。为了研究MIRTD的功能，我们建立了人神经母细胞瘤SH-SY 5 Y细胞，表达一种特异性抑制MIRTD mRNA的核酶--最大酶。大酶的表达特异性地消除了MIRTD蛋白，并且所得MIRTD缺陷细胞表现出线粒体呼吸链的复合物I和IV的亚基的量显著减少，导致活性下降。脉冲标记实验表明，亚基的丢失是一个翻译后事件。因此，DLST基因是双功能的，从该基因转录的MIRTD有助于线粒体呼吸复合物的生物发生。
Dihydrolipoamide succinyltransferase (DLST) is a subunit enzyme of the a-ketoglutarate dehydrogenase complex of the Krebs cycle. While studying how the DLST genotype contributes to the pathogenesis of Alzheimer's disease (AD), we found a novel mRNA that is transcribed starting from intron 7 in the DLST gene. The novel mRNA level in the brain of AD patients was significantly lower than that of controls. The truncated gene product (designated MIRTD) localized to the intermembrane space of mitochondria. To investigate the function of MIRTD, we established human neuroblastoma SH-SY5Y cells expressing a maxizyme, a kind of ribozyme, that specifically digests the MIRTD mRNA. The expression of the maxizyme specifically eliminated the MIRTD protein and the resultant MIRTD-deficient cells exhibited a marked decrease in the amounts of subunits of complexes I and IV of the mitochondrial respiratory chain, resulting in a decline of activity. A pulse-label experiment revealed that the loss of the subunits is a post-translational event. Thus, the DLST gene is bifunctional and MIRTD transcribed from the gene contributes to the biogenesis of the mitochondrial respiratory complexes.