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Human Molecular Genetics Advance Access originally published online on January 30, 2006
Human Molecular Genetics 2006 15(6):897-904; doi:10.1093/hmg/ddl007
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Acquisition of the wobble modification in mitochondrial tRNALeu(CUN) bearing the G12300A mutation suppresses the MELAS molecular defect

Yohei Kirino1,2, Takehiro Yasukawa1,3, Sanna K. Marjavaara4,{dagger}, Howard T. Jacobs4,5, Ian J. Holt3, Kimitsuna Watanabe1,2,{ddagger} and Tsutomu Suzuki1,2,*

1Department of Chemistry and Biotechnology, Graduate School of Engineering and 2Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan, 3MRC-Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, UK, 4Institute of Medical Technology and Tampere University Hospital, University of Tampere, Tampere FI-33014, Finland and 5Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, UK

* To whom correspondence should be addressed. Tel: +81 358418752; Fax: +81 338160106; Email: ts{at}chembio.t.u-tokyo.ac.jp

Received December 13, 2005; Accepted January 26, 2006

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 ({tau}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 acquires de novo {tau}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.

{dagger} Present address: Neuroscience Research Programme, Biomedicum Helsinki, University of Helsinki, FI-00014 Helsinki, Finland.

{ddagger} Present address: Biological Information Research Center (BIRC), National Institute of Advanced Industrial Science and Technology (AIST), 2-41-6 Aomi, Koto-ku, Tokyo 135-0064, Japan.


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