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MtDNA mutation in MERRF syndrome causes defective aminoacylation of tRNALys and premature translation termination


We have investigated the pathogenetic mechanism of the mitochondrial tRNALys gene mutation (position 8344) associated with MERRF encephalomyopathy in several mitochondrial DMA (mtDNA)–less cell transformants carrying the mutation and in control cells. A decrease of 50–60% in the specific tRNALys aminoacylation capacity per cell was found in mutant cells. Furthermore, several lines of evidence reveal that the severe protein synthesis impairment in MERRF mutation–carrying cells is due to premature termination of translation at each or near each lysine codon, with the deficiency of aminoacylated tRNALys being the most likely cause of this phenomenon.

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  1. Wallace, D.C. Diseases of the mitochondrial DMA. A. Rev. Biochem. 61, 1175–1212 (1992).

    Article  CAS  Google Scholar 

  2. Shoffner, J.M. et al. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DMA tRNALys mutation. Cell 61, 931–937 (1990).

    Article  CAS  PubMed  Google Scholar 

  3. Chomyn, A. et al. In vitro genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathy-patient mitochondria. Molec. cell Biol. 11, 2236–2244 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Boulet, L., Karpati, G. & Shoubridge, E.A. Distribution and threshold expression of the tRNALys mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF). Am. J. hum. Genet. 51, 1187–1200 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Yoneda, M., Miyatake, T. & Attardi, G. Complementation of mutant and wild-type human mitochondrial DMAs coexisting since the mutation event and lack of complementation of DMAs introduced separately into a cell within distinct organelles. Molec. cell Biol. 14, 2699–2712 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wallace, D.C. et al. Familial mitochondrial encephalomyopathy (MERRF): Genetic, pathophysiological, and biochemical characterization of a mitochondrial DMA disease. Cell 55, 601–610 (1988).

    Article  CAS  PubMed  Google Scholar 

  7. King, M.P. & Attardi, G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246, 500–503 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. King, M.P. & Attardi, G. Post-transcriptional regulation of the steady-state levels of mitochondrial transfer RNAs in HeLa cells. J. biol. Chem. 268, 10228–10237 (1993).

    CAS  PubMed  Google Scholar 

  9. Ojala, D., Montoya, J., & Attardi, G. tRNA punctuation model of RNA processing in human mitochondria. Nature 290, 470–474 (1981).

    Article  CAS  PubMed  Google Scholar 

  10. Attardi, G., Doersen, C., Gaines, G., King, M. & Montoya, J. New insights into the mechanisms of RNA synthesis and processing in human mitochondria in Achievements and Perspectives in Mitochondrial Research, vol. II (eds E. Quagliarello etal.) 145–163, (Elsevier, Amsterdam, 1985).

    Google Scholar 

  11. Varshney, U., Lee, C.-P & RajBhandary, U.L. Direct analysis of aminoacylation levels of tRNAs in vivo. J. biol. Chem. 266, 24712–24718 (1991).

    CAS  PubMed  Google Scholar 

  12. Attardi, G. Animal mitochondrial DNA: An extreme example of genetic economy. Int. Rev. Cyt. 93, 93–145 (1985).

    Article  CAS  Google Scholar 

  13. Anderson, S. et al. Sequence and organization of the human mitochondrial genome. Nature 290, 427–465 (1981).

    Google Scholar 

  14. Cleveland, D.W., Fischer, S.G., Kirschner, M.W. & Laemmli, U.K. Peptide mapping by limited proteolysis in sodium dodecyl sulfate and analysis by gel electrophoresis. J. biol. Chem. 252, 1102–1106 (1977).

    CAS  PubMed  Google Scholar 

  15. Mariottini, P., Chomyn, A., Riley, M., Cottrell, B., Doolittle, R.F. & Attardi, G. Identification of the polypeptides encoded in the unassigned reading frames 2,4,4L and 5 of human mitochondrial DNA. Proc. natn. Acad. Sci. U.S.A. 83, 1563–1567 (1986).

    Article  CAS  Google Scholar 

  16. Attardi, G. & Ojala, D. Mitochondrial ribosomes in HeLa cells. Nature new Biol. 229, 133–136 (1971).

    Article  CAS  PubMed  Google Scholar 

  17. Ojala, D. & Attardi, G. Expression of the mitochondrial genome in HeLa cells. X. Properties of mitochondrial polysomes. J. molec. Biol. 65, 273–289 (1972).

    Article  CAS  PubMed  Google Scholar 

  18. Attardi, B., Cravioto, B. & Attardi, G. Membrane-bound ribosomes in HeLa cells. I. Their proportion to total cell ribosomes and their association with messenger RNA. J. molec. Biol. 44, 47–70 (1969).

    Article  CAS  PubMed  Google Scholar 

  19. Nierhaus, K.H., Franceschi, F., Subramanian, A.R., Erdmann, V.A. & Wittmann-Liebold, B. (eds). The translation apparatus: Structure, function, regulation, evolution. (Plenum Press, New York 1993).

    Book  Google Scholar 

  20. Normanly, J. & Abelson, J. tRNA identity. A Rev. Biochem. 58, 1029–1049 (1989).

    Article  CAS  Google Scholar 

  21. Schimmel, P., Giegé, R., Moras, D. & Yokoyama, S. An operational RNA code for amino acids and possible relationship to genetic code. Proc. natn. Acad. Sci. U.S.A. 90, 8763–8768 (1993).

    Article  CAS  Google Scholar 

  22. Saks, M.E., Sampson, J.R. & Abelson, J.N. The transfer RNA identity problem: a search for rules. Science 263, 191–197 (1994).

    Article  CAS  PubMed  Google Scholar 

  23. Giegé, R., Puglisi, J.D. & Florentz, C. tRNA structure and aminoacylation efficiency. Progr. nucl. Acid Res. Molec. Biol. 45, 129–206 (1993).

    Article  Google Scholar 

  24. Kurland, C.G. Translational accuracy and the fitness of bacteria. A. Rev. Genet. 26, 29–50 (1992).

    Article  CAS  Google Scholar 

  25. Kurland, C.G. & Gallant, J.A. The secret life of the ribosome. In “Accuracy in Molecular Processes”(eds Kirkwood, T.B.L, Rosenberger, R.F. & Galas, D. J.), 127–157 (Chapman and Hall, London, 1986).

    Chapter  Google Scholar 

  26. Hayashi, J.I. et al. Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction. Proc. natn. Acad. Sci. U.S.A. 88, 10614–10618 (1991).

    Article  CAS  Google Scholar 

  27. Amaldi, F. & Attardi, G. Partial sequence analysis of ribosomal RNA from HeLa cells. I. Oligonucleotide pattern of 28S and 18S RNA after pancreatic ribonuclease digestion. J. molec. Biol. 33, 737–755 (1968).

    Article  CAS  PubMed  Google Scholar 

  28. Gaines, G. & Attardi, G. Highly efficient RNA-synthesizing system that uses isolated human mitochondria: New initiation events and in vivo-like processing patterns. Molec. cell. Biol. 4, 1605–1617 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lynch, D.C. & Attardi, G. Amino acid specificity of the transfer RNA species coded for by HeLa cell mitochondrial DNA. J. molec. Biol. 102, 125–141 (1976).

    Article  CAS  PubMed  Google Scholar 

  30. Chomyn, A. et al. MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts. Proc. natn. Acad. Sci. U.S.A. 89, 4221–4225.

    Article  CAS  Google Scholar 

  31. Feinberg, A.P. & Vogelstein, B.A. technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal. Biochem. 132, 6–13 (1983).

    Article  CAS  PubMed  Google Scholar 

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Enriquez, J., Chomyn, A. & Attardi, G. MtDNA mutation in MERRF syndrome causes defective aminoacylation of tRNALys and premature translation termination. Nat Genet 10, 47–55 (1995).

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