Reduction of mitochondrial tRNALeu(UUR) aminoacylation by some MELAS-associated mutations

Hao, Rui; Yao, Yong-Neng; Zheng, Yong-Gang; Xu, Min-Gang; Wang, En-Duo

doi:10.1016/j.febslet.2004.11.004

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Volume 578, Issue 1 , Pages 135-139, 3 December 2004

Reduction of mitochondrial tRNA^Leu(UUR) aminoacylation by some MELAS-associated mutations

Edited by Horst Feldmann

Rui Hao
- State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Chinese Academy of Sciences, PR China
- Graduate School of the Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, PR China
Yong-Neng Yao
- State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Chinese Academy of Sciences, PR China
Yong-Gang Zheng
- State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Chinese Academy of Sciences, PR China
Min-Gang Xu
- State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Chinese Academy of Sciences, PR China
En-Duo Wang
- State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Chinese Academy of Sciences, PR China
- Corresponding author. Fax: +86 21 54921011

Received 1 October 2004; received in revised form 30 October 2004; accepted 3 November 2004. published online 17 November 2004.

Abstract

The mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome (MELAS) is a rare congenital disorder of mitochondrial DNA. Five single nucleotide substitutions within the human mitochondrial tRNA^Leu(UUR) gene have been reported to be associated with MELAS. Here, we provide in vitro evidence that the aminoacylation capacities of these five hmtRNA^Leu(UUR) transcripts are reduced to different extents relative to the wild-type hmtRNA^Leu(UUR) transcript. A thermal denaturation experiment showed that the A3243G and T3291C mutants, which were the least charged by LeuRS, have fragile structures. In addition, the T3291C mutant can inhibit aminoacylation of the wild-type hmtRNA^Leu(UUR), indicating that it may act as an inhibitor in the mitochondrial heteroplasmic environment.

Abbreviations: MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome, hmLeuRS, human mitochondrial leucyl-tRNA synthetase, hmtRNA, human mitochondrial tRNA, hmDNA, human mitochondrial DNA, E. coli, Escherichia coli