Aminoacyl-tRNA synthetases (aaRSs), key enzymes in translation, catalyze the specific attachment of each amino acid (aa) to the cognate tRNA(s). With few exceptions, there are 20 aaRSs in each of the translation machineries of any organism. Animal eukaryotic cells have two coding genomes: the nuclear DNA whose mRNAs are translated into the cytosol, and the mitochondrial (mt) DNA, transcribed and translated in the mitochondria. Interestingly, mt genomes accumulate mutations at far greater rates than nuclear genomes, leading to the need for reciprocal molecular adaptation(s) between mt-DNA encoded and nuclear-DNA encoded mitochondrial molecules.

Mitochondria are the platforms of many major functions in eukaryotic cells such as respiration, energy production in the form of ATP, or the biosynthesis of metabolites. Mitochondrial dysfunctions are associated in humans with various neurodegenerative and muscular pathologies. These organelles are equally essential in all eukaryotes including kinetoplastids, which are parasitic unicellular eukaryotes (e.g. leishmanias and trypanosomatidae) responsible for serious pathologies, potentially lethal for mammals including humans. Human mt-DNA encodes 13 proteins and the kinetoplast maxicircle DNA of trypanosomatids encodes 18 proteins, all functional components of the respiratory chain complexes. While mt-tRNAs are transcribed from the mt-DNA in humans, they are all imported from the nucleus into kinetoplastids. All mt-aaRSs are encoded by the nucleus, but from genes that are either mostly distinct in humans or mostly common in kinetoplastids from those coding for the cytosolic aaRSs. Mt-addressed proteins have an N-terminal targeting sequence (MTS), cleaved after import by a process poorly defined but essential for protein’s delivery and functionality (see Figure).

mrna-translation-mitochondria-figure

The general objectives are to decipher the structure/function relationships of macromolecules forming the translation machinery in healthy as well as under pathological contexts. Focuses are made on mitochondrial aminoacylation systems [tRNAs and aminoacyl-tRNA synthetases (aaRSs)], using approaches combining mainly biochemistry, molecular and cellular biology, and bioinformatic.

In this scientific context, the main objectives are:

  1. To decipher the structural and functional peculiarities of mitochondrial aminoacyl-tRNA synthetases in human and in kinetoplastids (mainly AspRSs and ArgRSs, the enzyme specific for the acid aspartic and the arginine, respectively).

  2. To identify the cellular properties of mitochondrial aminoacyl-tRNA synthetases (maturation site(s) after importation, sub-mitochondrial localization(s), tissue-specific properties/functions, partnership, …).

  3. To address aaRSs-related mitochondrial disorders (see http://www.misynpat.org).

  4. To envision kinetoplastids mt-aaRSs as possible targets of choice for the fight against infections related to parasitic kinetoplastis