Mitochondrial biogenesis dysfunction and metabolic dysfunction from a novel mitochondrial tRNA(Met) 4467 C>A mutation in a Han Chinese family with maternally inherited hypertension.
Mitochondrial biogenesis dysfunction and metabolic dysfunction from a novel mitochondrial tRNA(Met) 4467 C>A mutation in a Han Chinese family with maternally inherited hypertension.
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DOI：
10.1038/s41598-017-03303-w
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发表时间：
2017-06-08
影响因子：
4.6
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Liu Y;Li Y;Zhu C;Tian L;Guan M;Chen Y
目的：探讨线粒体DNA(MtDNA)与高血压的关系及其参与线粒体代谢功能障碍的机制。我们在一个汉族高血压家系中发现了一个新的tRNAMet C4467A突变。与非母亲成员相比，母亲成员的血糖、总胆固醇、低密度脂蛋白和血钠升高，而钾降低(P <； 0.05)。分离分析表明该突变为母系遗传。我们分析了来自三个母亲家庭成员和三个非母亲家庭成员的淋巴细胞株。与对照组相比，突变细胞系的活性氧产生增加114.5%(P <；ATP0.05)，而 降低26.4%。突变细胞系线粒体膜电位较对照组降低26.2%(P <； 0.05)。突变细胞系的氧耗率降低(P <； 0.05)。突变细胞株中Caspase-3/7的活性比对照细胞株高104.1%(P <； )。突变细胞株中电压依赖性阴离子通道(VDAC)、Bax和凋亡诱导因子(AIF)的表达均高于对照组，且VDAC和Bax共定位增加。因此，该突变导致氧化应激和线粒体生物发生功能障碍，可能参与高血压的发病机制。
To investigate the relationship between mitochondrial DNA (mtDNA) and hypertension as well as the mechanism involved in mitochondrial metabolic dysfunction. We identified a novel tRNAMet C4467A mutation in a Han Chinese family with hypertension. The maternal members presented with increased glucose, total cholesterol, low-density lipoprotein, and serum sodium as well as decreased potassium compared with non-maternal members (P < 0.05). Segregation analysis showed this mutation was maternally inherited. We analyzed lymphocyte cell lines derived from three maternal and three non-maternal family members. Reactive oxygen species production in the mutant cell lines was 114.5% higher compared with that in controls (P < 0.05) while ATP was 26.4% lower. The mitochondrial membrane potential of the mutated cell lines was 26.2% lower than that in controls (P < 0.05). Oxygen consumption rates were decreased in the mutant cell lines (P < 0.05). The activation of caspase-3/7 was 104.1% higher in the mutant cell lines compared with controls (P < 0.05). The expression of voltage-dependent anion channel (VDAC), Bax and apoptosis-inducing factor (AIF) in the mutant cell lines was higher compared with that in controls, with the increased colocalization of VDAC and Bax. Therefore, this mutation contributes to oxidative stress and mitochondrial biogenesis dysfunction, which may be involved in the pathogenesis of hypertension.