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A Hypertension-Associated tRNAAla Mutation Alters tRNA Metabolism and Mitochondrial Function

机译：高血压相关的tRNAAla突变改变tRNA代谢和线粒体功能。

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In this report, we investigated the pathophysiology of a novel hypertension-associated mitochondrial tRNAAla 5655A → G (m.5655A → G) mutation. The destabilization of a highly conserved base pairing (A1-U72) at the aminoacyl acceptor stem by an m.5655A → G mutation altered the tRNAAla function. An in vitro processing analysis showed that the m.5655A → G mutation reduced the efficiency of tRNAAla precursor 5′ end cleavage catalyzed by RNase P. By using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from a Chinese family into mitochondrial DNA (mtDNA)-less (ρo) cells, we showed a 41% reduction in the steady-state level of tRNAAla in mutant cybrids. The mutation caused an improperly aminoacylated tRNAAla, as suggested by aberrantly aminoacylated tRNAAla and slower electrophoretic mobility of mutated tRNA. A failure in tRNAAla metabolism contributed to variable reductions in six mtDNA-encoded polypeptides in mutant cells, ranging from 21% to 37.5%, with an average of a 29.1% reduction, compared to levels of the controls. The impaired translation caused reduced activities of mitochondrial respiration chains. Furthermore, marked decreases in the levels of mitochondrial ATP and membrane potential were observed in mutant cells. These caused increases in the production of reactive oxygen species in the mutant cybrids. The data provide evidence for the association of the tRNAAla 5655A → G mutation with hypertension.
机译：在本报告中，我们研究了一种新的与高血压相关的线粒体tRNA Ala 5655A→G（​​m.5655A→G）突变的病理生理。 m.5655A→G突变使氨酰基受体茎上高度保守的碱基配对（A1-U72）不稳定，从而改变了tRNA Ala 功能。 体外加工分析表明，m.5655A→G突变降低了RNase P催化的tRNA Ala 前体5'末端切割的效率。来自中国家庭的淋巴母细胞细胞系的线粒体进入少线粒体DNA（mtDNA）（ρ o ）细胞，我们发现tRNA Ala < / sup>在突变体cybrids中。突变导致不正确的氨基酰化tRNA Ala ，这是由于异常的氨酰化tRNA Ala 和突变的tRNA的电泳迁移速度较慢所致。与对照水平相比，tRNA Ala 代谢失败导致突变细胞中六种mtDNA编码多肽的可变减少，范围从21％至37.5％，平均减少29.1％ 。翻译受损导致线粒体呼吸链活性降低。此外，在突变细胞中观察到线粒体ATP水平和膜电位的显着降低。这些导致突变的杂种中活性氧的产生增加。这些数据为tRNA Ala 5655A→G突变与高血压的相关性提供了证据。

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