title: Multilevel functional and structural defects induced by two pathogenic mitochondrial tRNA mutations.
abstract: Point mutations in hmtRNAs (human mitochondrial tRNAs) can cause various disorders, such as CPEO (chronic progressive external ophthalmoplegia) and MM (mitochondrial myopathy). Mitochondrial tRNALeu, especially the UUR codon isoacceptor, is recognized as a hot spot for pathogenic mtDNA point mutations. Thus far, 40 mutations have been reported in hmtRNAsLeu. In the present paper, we describe the wide range of effects of two substitutions found in the TΨC arms of two hmtRNAsLeu isoacceptors. The G52A substitution, corresponding to the pathogenic G12315A mutation in tRNALeu(CUN), and G3283A in tRNALeu(UUR) exhibited structural changes in the outer corner of the tRNA shape as shown by RNase probing. These mutations also induced reductions in aminoacylation, 3'-end processing and base modification processes. The main effects of the A57G substitution, corresponding to mutations A12320G in tRNALeu(CUN) and A3288G in tRNALeu(UUR), were observed on the aminoacylation activity and binding to hmEF-Tu (human mitochondrial elongation factor Tu). These observations suggest that the wide range of effects may amplify the deleterious impact on mitochondrial protein synthesis in vivo. The findings also emphasize that an exact understanding of tRNA dysfunction is critical for the future development of therapies for mitochondrial diseases.
authors: Center for RNA Research, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Chinese Academy of Sciences, Shanghai 200031, People's Republic of China.
authors: Meng
authors: M
authors: Wang
authors: Xiao-Long
authors: XL
authors: Zhou
authors: Ru-Juan
authors: RJ
authors: Liu
authors: Zhi-Peng
authors: ZP
authors: Fang
authors: Mi
authors: M
authors: Zhou
authors: Gilbert
authors: G
authors: Eriani
authors: En-Duo
authors: ED
authors: Wang
mesh_terms: D004272:DNA, Mitochondrial / Q000235:genetics*; D006801:Humans; D007625:Kearns-Sayre Syndrome / Q000235:genetics; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism; D017240:Mitochondrial Myopathies / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010444:Peptide Elongation Factor Tu / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D012316:RNA Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism; D012343:RNA, Transfer / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D012343:RNA, Transfer; D012316:RNA Nucleotidyltransferases; C023198:tRNA nucleotidyltransferase; D010444:Peptide Elongation Factor Tu