Human Molecular Genetics Advance Access published online on January 30, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl007
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan; Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
* To whom correspondence should be addressed. The A3243G mutation in the mitochondrial gene for human mitochondrial (mt) tRNALeu(UUR), responsible for decoding of UUR codons, is associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). We previously demonstrated that this mutation causes defects in 5-taurinomethyluridine (
Received December 13, 2005
Revised January 26, 2006
Accepted January 26, 2006
Article
Acquisition of the wobble modification in mitochondrial tRNALeu(CUN) bearing the G12300A mutation suppresses the MELAS molecular defect
Yohei Kirino 1,
Takehiro Yasukawa 2,
Sanna K. Marjavaara 3,
Howard T. Jacobs 4,
Ian J. Holt 5,
Kimitsuna Watanabe 1,
and
Tsutomu Suzuki 1 *
2 Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan; MRC-Dunn Human Nutrition Unit, Hills Road, Cambridge, CB2 2XY, United Kingdom
3 Institute of Medical Technology and Tampere University Hospital, FI-33014 University of Tampere, Finland
4 Institute of Medical Technology and Tampere University Hospital, FI-33014 University of Tampere, Finland; Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom
5 MRC-Dunn Human Nutrition Unit, Hills Road, Cambridge, CB2 2XY, United Kingdom
Tsutomu Suzuki, E-mail: ts{at}chembio.t.u-tokyo.ac.jp
Abstract 
m5U) modification at the anticodon first (wobble) position of the mutant mt tRNALeu(UUR), leading to a UUG decoding deficiency and entraining severe respiratory defects. In addition, we previously identified a heteroplasmic mutation, G12300A, in the other mt leucine tRNA gene, mt tRNALeu(CUN), which functions as a suppressor of the A3243G respiratory defect in cybrid cells containing A3243G mutant mtDNA. Although the G12300A mutation converts the anticodon sequence of mt tRNALeu(CUN) from UAG to UAA, this tRNA carrying an unmodified wobble uridine still cannot decode the UUG codon. Mass spectrometric analysis of the suppressor mt tRNALeu(CUN) carrying the G12300A mutation from the phenotypically revertant cells revealed that the wobble uridine aquires de novo m5U modification. In vitro translation confirmed the functionality of the suppressor tRNA for decoding UUG codons. These results demonstrate that the acquisition of the wobble modification in another isoacceptor tRNA is critical for suppressing the MELAS mutation, and they highlight the primary role of the UUG decoding deficiency in the molecular pathogenesis of MELAS syndrome.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Villarroya, S. Prado, J. M. Esteve, M. A. Soriano, C. Aguado, D. Perez-Martinez, J. I. Martinez-Ferrandis, L. Yim, V. M. Victor, E. Cebolla, et al. Characterization of Human GTPBP3, a GTP-Binding Protein Involved in Mitochondrial tRNA Modification Mol. Cell. Biol., December 15, 2008; 28(24): 7514 - 7531. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M.C. Janssen, P. J. Hensbergen, F. J. van Bussel, C. I.A. Balog, J. A. Maassen, A. M. Deelder, and A. K. Raap The A3243G tRNALeu(UUR) mutation induces mitochondrial dysfunction and variable disease expression without dominant negative acting translational defects in complex IV subunits at UUR codons Hum. Mol. Genet., October 15, 2007; 16(20): 2472 - 2481. [Abstract] [Full Text] [PDF]
|
|