Human Molecular Genetics Advance Access published online on August 18, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh267
© 2004 by Oxford University Press
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1 CNRS-FRE 2375 "Yeast Models for Human Pathologies" and Université Louis Pasteur, Institute of Physiology and Biological Chemistry, 21 René Descartes, 67084 Strasbourg, France; Dept of Molecular Biology, Biology Faculty, Moscow State University, 119992 Moscow, Russia; Mitochondrial Research Group, Medical School, Neurology Department, University of Newcastle upon Tyne, Framlington Place, NE2 4HH Newcastle upon Tyne, United Kingdom
* To whom correspondence should be addressed. E-mail: i.tarassov{at}ibmc.u-strasbg.fr.
Mitochondrial DNA mutations are an important cause of human disease for which there is no efficient treatment. Our aim was to determine whether the A8344G mitochondrial tRNALys mutation, which can cause the MERRF (Myoclonic Epilepsy with Ragged-Red Fibers) syndrome could be complemented by targetting tRNAs into mitochondria from the cytosol. Import of small RNAs into mitochondria has been demonstrated in many organisms, including protozoans, plants, fungi and animals. Although human mitochondria do not import tRNAs in vivo, we previously demonstrated that some yeast tRNA derivatives can be imported into isolated human mitochondria. We show here that yeast tRNAsLys derivatives expressed in immortalised human cells and in primary human fibroblasts are partially imported into mitochondria. Imported tRNAs are correctly aminoacylated and are able to participate in mitochondrial translation. In transmitochondrial cybrid cells and in patient-derived fibroblasts bearing the MERRF mutation, import of tRNALys is accompanied by a partial rescue of mitochondrial functions affected by the mutation such as mitochondrial translation, activity of respiratory complexes, electrochemical potential across the mitochondrial membrane and respiration rate. Import of a tRNALys with a mutation in the anticodon preventing recognition of the Lysine codons do not lead to any rescue, while downregulation of the transgenic tRNAs by siRNA transiently abolishes the functional rescue, showing that this rescue is due to the import. These findings prove for the first time the functionality of imported tRNAs in human mitochondria in vivo and highlight the potential for exploiting the RNA import pathway to treat patients with mtDNA diseases.
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Nuclear DNA-encoded tRNAs targeted into mitochondria can rescue a mitochondrial DNA mutation associated with the MERRF syndrome in cultured human cells
2 CNRS-FRE 2375 "Yeast Models for Human Pathologies" and Université Louis Pasteur, Institute of Physiology and Biological Chemistry, 21 René Descartes, 67084 Strasbourg, France
3 Mitochondrial Research Group, Medical School, Neurology Department, University of Newcastle upon Tyne, Framlington Place, NE2 4HH Newcastle upon Tyne, United Kingdom
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