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Intracellular traffic of RNA and mitochondrial diseases

The team studies are focused on different aspects od the phenomenon of targeting macromolecules (essentially RNAs) into mitochondria and to the exploitation of these pathways for development of new gene therapy approaches to mitochondrial diseases. Human cells and yeast S. cerevisiae are used as main models.

In yeast, one of the tRNA-Lys (tRK1) is coded by nuclear genes and partially addressed '"imported" into mitochondria. We uncovered the mechanism of this import, implicating two proteins, a glycolytic enzyme enolase-2 and the cytoplasmic precursor of the mitochondrial lysyl-tRNA synthetase, pre-Msk1p, which act as RNA-chaperone and the cargo-carrier, respectively (Genes & Dev., 2006










We have demonstrated that the imported tRNA have a conditional function in the organelle: in conditions of thermic stress, the mitochondrial DNA coded tRNA-Lys (tRK3) is hypomodified and becomes inefficient in recognition of one out of the two Lysine codons, while the imported tRK1 is able to restore the normal mitochondrial translation (Mol. Cell, 2007


In humans, 5S ribosomal RNA is also imported into mitochondria. We have identified the elements that determine the specificity of the import and proposed a mechanism by which the repartition of this RNA between nuclear and mitochondrial compartments of the cell implicate competition between mitochondrial targeting factors and factors of nuclear re-import (essentially the L5 protein) (RNA, 2008 Furthermore, we found that several yeast tRNA and their mutated derivatives are able to be imported into human mitochondria in an artificial way (J. Biol. Chem., 2001, which demonstrate an amazing flexibility of the import pathway.

The second direction of our studies aims to exploit these mechanisms to address into mitochondria RNA molecules with therapeutic activities. Mitochondrial DNA mutations are often at the origin of severe neuro-muscular diseases, which, up to now, have no efficient treatment.


We first validated our strategy in yeast, by complementing the respiratory defect caused by a non-sense mutation in mitochondrial DNA by a suppressor tRNA expressed in the nucleus and targeted into the organelle (Science, 2000, Next, we successfully tested the same approach in human cells by partial complementation of a mitochondrial deficiency caused by a mutation in the mitochondrial tRNA-Lys gene, commonly associated with the MERRF syndrome (Myoclonic Epilepsy with Red Ragged Fibers) by imported specifically designed tRNAs (Human Mol. Genet., 2004