التفاصيل البيبلوغرافية
| العنوان: |
A Hypertension-Associated tRNAAla Mutation Alters tRNA Metabolism and Mitochondrial Function. |
| المؤلفون: |
Pingping Jiang, Meng Wang, Ling Xue, Yun Xiao, Jialing Yu, Hui Wang, Juan Yao, Hao Liu, Yanyan Peng, Hanqing Liu, Haiying Li, Ye Chen, Min-Xin Guan |
| المصدر: |
Molecular & Cellular Biology; Jul2016, Vol. 36 Issue 14, p1920-1930, 11p |
| مصطلحات موضوعية: |
HYPERTENSION, AMINOACYL-tRNA, GENETIC mutation, PATHOLOGICAL physiology, LYMPHOBLASTOID cell lines, MEMBRANE potential, MITOCHONDRIAL DNA |
| مستخلص: |
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 (ρ°) 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. [ABSTRACT FROM AUTHOR] |
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