The deafness-associated mitochondrial DNA mutation at position 7445, which affects tRNASer(UCN) precursor processing, has long-range effects on NADH dehydrogenase subunit ND6 gene expression
The deafness-associated mitochondrial DNA mutation at position 7445, which affects tRNASer(UCN) precursor processing, has long-range effects on NADH dehydrogenase subunit ND6 gene expression
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DOI：
10.1128/mcb.18.10.5868
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发表时间：
1998-10-01
影响因子：
5.3
通讯作者：
Attardi, G
中科院分区：
文献类型：
--
作者：
Guan, MX;Enriquez, JA;Attardi, G
发病机制的恶性相关的线粒体DNA（mtDNA）T7445 C突变已在几个淋巴母细胞样细胞系的成员，新西兰的系谱表现出同质形式的突变和控制个人进行了研究。我们在这里表明，突变银行的3'末端的tRNA（Ser（UCN））基因序列，并影响的速度，但不影响网站的加工tRNA前体。这导致分析的细胞系中tRNA（Ser（UCN））水平平均降低约70%，蛋白质合成速率降低约45%。数据显示tRNA（Ser（UCN））支持野生型蛋白质合成速率的能力的明显阈值，其对应于该tRNA的对照水平的40%。引人注目的是，在NADH脱氢酶（复合物I）ND 6亚基基因的mRNA水平中观察到7445突变相关的显著降低，该基因位于上游7 kbp附近，与tRNA（Ser（UCN））基因共转录，有力的证据表明与tRNA前体加工缺陷存在机械联系。这种减少显著影响ND 6亚基的合成速率，并在突变细胞系的生育相关呼吸表型中起决定性作用。特别是，它占他们的具体的，非常显着的减少谷氨酸或苹果酸依赖的O-2消耗此外，几个同质mtDNA突变影响亚基的NADH脱氢酶可能发挥协同作用，在建立呼吸表型的突变细胞。
The pathogenetic mechanism of the deafness-associated mitochondrial DNA (mtDNA) T7445C mutation has been investigated in several lymphoblastoid cell lines from members of a New Zealand pedigree exhibiting the mutation in homoplasmic form and from control individuals. We show here that the mutation Banks the 3' end of the tRNA(Ser(UCN)) gene sequence and affects the rate but not the sites of processing of the tRNA precursor. This causes an average reduction of similar to 70% in the tRNA(Ser(UCN)) level and a decrease of similar to 45% in protein synthesis rate in the cell lines analyzed. The data show a sharp threshold in the capacity of tRNA(Ser(UCN)) to support the wild-type protein synthesis rate, which corresponds to similar to 40% of the control level of this tRNA. Strikingly, a 7445 mutation-associated marked reduction has been observed in the level of the mRNA for the NADH dehydrogenase (complex I) ND6 subunit gene, which is located similar to 7 kbp upstream and is cotranscribed with the tRNA(Ser(UCN)) gene, with strong evidence pointing to a mechanistic link with the tRNA precursor processing defect. Such reduction significantly affects the rate of synthesis of the ND6 subunit and plays a determinant role in the deafness-associated respiratory phenotype of the mutant cell lines. In particular, it accounts for their specific, very significant decrease in glutamate- or malate-dependent O-2 consumption Furthermore, several homoplasmic mtDNA mutations affecting subunits of NADH dehydrogenase may play a synergistic role in the establishment of the respiratory phenotype of the mutant cells.