Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China.
Circ Res. 2011 Apr 1;108(7):862-70. doi: 10.1161/CIRCRESAHA.110.231811.
Despite maternal transmission of hypertension in some pedigrees, pathophysiology of maternally inherited hypertension remains poorly understood.
To establish a causative link between mitochondrial dysfunction and essential hypertension.
A total of 106 subjects from a large Chinese family underwent clinical, genetic, molecular, and biochemical evaluations. Fifteen of 24 adult matrilineal relatives exhibited a wide range of severity in essential hypertension, whereas none of the offspring of affected fathers had hypertension. The age at onset of hypertension in the maternal kindred varied from 20 years to 69 years, with an average of 44 years. Mutational analysis of their mitochondrial genomes identified a novel homoplasmic 4263A>G mutation located at the processing site for the tRNA(Ile) 5'-end precursor. An in vitro processing analysis showed that the 4263A>G mutation reduced the efficiency of the tRNA(Ile) precursor 5'-end cleavage catalyzed by RNase P. tRNA Northern analysis revealed that the 4263A>G mutation caused ≈46% reduction in the steady-state level of tRNA(Ile). An in vivo protein-labeling analysis showed ≈32% reduction in the rate of mitochondrial translation in cells carrying the 4263A>G mutation. Impaired mitochondrial translation is apparently a primary contributor to the reductions in the rate of overall respiratory capacity, malate/glutamate-promoted respiration, succinate/glycerol-3-phosphate-promoted respiration, or N,N,N',N'-tetramethyl-p-phenylenediamine/ascorbate-promoted respiration and the increasing level of reactive oxygen species in cells carrying the 4263A>G mutation.
These data provide direct evidence that mitochondrial dysfunction caused by mitochondrial tRNA(Ile) 4263A>G mutation is involved in essential hypertension. Our findings may provide new insights into pathophysiology of maternally transmitted hypertension.
尽管在一些家族中高血压可通过母体遗传，但母体遗传性高血压的病理生理学仍知之甚少。
确定线粒体功能障碍与原发性高血压之间的因果关系。
对一个中国大家族的 106 名成员进行了临床、遗传、分子和生化评估。24 名成年母系亲属中，有 15 人患有原发性高血压，严重程度不一，而患病父亲的后代无一患有高血压。该母系家族中高血压的发病年龄从 20 岁到 69 岁不等，平均为 44 岁。对其线粒体基因组进行突变分析，发现一个新的同质突变 4263A>G，位于 tRNA(Ile)5′-末端前体的加工位点。体外加工分析显示，4263A>G 突变降低了 RNase P 催化 tRNA(Ile)前体 5′-末端切割的效率。tRNA Northern 分析显示，4263A>G 突变导致 tRNA(Ile)的稳态水平降低约 46%。体内蛋白标记分析显示，携带 4263A>G 突变的细胞中线粒体翻译的速度降低了约 32%。线粒体翻译受损显然是导致携带 4263A>G 突变的细胞中整体呼吸能力、苹果酸/谷氨酸促进的呼吸、琥珀酸/甘油-3-磷酸促进的呼吸或 N,N,N',N'-四甲基-p-苯二胺/抗坏血酸促进的呼吸速率降低以及活性氧水平升高的主要原因。
这些数据提供了直接证据，表明线粒体 tRNA(Ile)4263A>G 突变引起的线粒体功能障碍与原发性高血压有关。我们的发现可能为母体遗传性高血压的病理生理学提供新的见解。
