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Int J Biol Sci 2018; 14(11):1437-1444. doi:10.7150/ijbs.27043

Research Paper

Overexpression of human mitochondrial alanyl-tRNA synthetase suppresses biochemical defects of the mt-tRNAAla mutation in cybrids

Xiaoxu Zhao1,2#, Jiamin Han1,2#, Ling Zhu1, Yun Xiao2, Chenghui Wang1,2, Fang Hong1, Pingping Jiang1,2✉, Min-Xin Guan1,2

1. Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
2. Institute of Genetics Zhejiang University, and Department of Human Genetics, Zhejiang University School of Medicine, Hangzhou, 310058, China.
# These two authors contributed equally to this work.

Abstract

Mutations of mitochondrial transfer RNAs (mt-tRNAs) play a major role in a wide range of mitochondrial diseases because of the vital role of these molecules in mitochondrial translation. It has previously been reported that the overexpression of mitochondrial aminoacyl tRNA synthetases is effective at partially suppressing the defects resulting from mutations in their cognate mt-tRNAs in cells. Here we report a detailed analysis of the suppressive activities of mitochondrial alanyl-tRNA synthetase (AARS2) on mt-tRNAAla 5655 A>G mutant. Mitochondrial defects in respiration, activity of oxidative phosphorylation complexes, ATP production, mitochondrial superoxide, and membrane potential were consistently rescued in m.5655A>G cybrids upon AARS2 expression. However, AARS2 overexpression did not result in a detectable increase in mutated mt-tRNAAla but caused an increase incharged mt-tRNAAla in mutant cybrids, leading to enhanced mitochondrial translation. This indicated that AARS2 improved the aminoacylation activity in the case of m.5655A>G, rather than having a stabilizing effect on the tRNA structure. The data presented in this paper deepen our understanding of the pathogenesis of mt-tRNA diseases.

Keywords: mitochondrial tRNA, mitochondrial alanyl-tRNA synthetase, cybrid, oxidative phosphorylation

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Zhao X, Han J, Zhu L, Xiao Y, Wang C, Hong F, Jiang P, Guan MX. Overexpression of human mitochondrial alanyl-tRNA synthetase suppresses biochemical defects of the mt-tRNAAla mutation in cybrids. Int J Biol Sci 2018; 14(11):1437-1444. doi:10.7150/ijbs.27043. Available from http://www.ijbs.com/v14p1437.htm