Modification defect at anticodon wobble nucleotide of mitochondrial tRNAsLeu(UUR) with pathogenic mutations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes

被引:227
作者
Yasukawa, T
Suzuki, T
Suzuki, T
Ueda, T
Ohta, S
Watanabe, K
机构
[1] Univ Tokyo, Grad Sch Engn, Dept Chem & Biotechnol, Bunkyo Ku, Tokyo 1138656, Japan
[2] Nippon Med Sch, Inst Gerontol, Dept Biochem & Cell Biol, Nakahara Ku, Kawasaki, Kanagawa 2110063, Japan
[3] Univ Tokyo, Grad Sch Frontier Sci, Dept Integrated Biosci, Bunkyo Ku, Tokyo 1138656, Japan
关键词
D O I
10.1074/jbc.275.6.4251
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The mitochondrial tRNA(Leu)(UUR) (R = A or Gr) gene possesses several hot spots for pathogenic mutations. A point:mutation at nucleotide position 3243 or 3271 is associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes and maternally inherited diabetes with deafness. Detailed studies on two tRNAs(Leu)(UUR) with the 3243 or 3271 mutation revealed some common characteristics in cybrid cells: (i) a decreased life span, resulting in a 70% decrease in the amounts of the tRNAs in the steady state, (ii) a slight decrease in the ratios of aminoacyl-tRNAs(Leu)(UUR) versus uncharged tRNAs(Leu)(UUR), and (iii) accurate aminoacylation with leucine without any misacylation. As a marked result, both of the mutant tRNA molecules were deficient in a modification of uridine that occurs in the normal tRNA(Leu)(UUR) at the first position of the anticodon, The lack of this modification may lead to the mistranslation of leucine into non-cognate phenylalanine codons by mutant tRNAsLeU(UUR), according to the mitochondrial wobble rule, and/or a decrease in the rate of mitochondrial protein synthesis. This finding could explain why two different mutations (3243 and 3271) manifest indistinguishable clinical features.
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页码:4251 / 4257
页数:7
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