Human mitochondrial leucyl tRNA synthetase can suppress non cognate pathogenic mt‐tRNA mutations

Disorders of the mitochondrial genome cause a wide spectrum of disease, these present mainly as neurological and/or muscle related pathologies. Due to the intractability of the human mitochondrial genome there are currently no effective treatments for these disorders. The majority of the pathogenic mutations lie in the genes encoding mitochondrial tRNAs. Consequently, the biochemical deficiency is due to mitochondrial protein synthesis defects, which manifest as aberrant cellular respiration and ATP synthesis. It has previously been reported that overexpression of mitochondrial aminoacyl tRNA synthetases has been effective, in cell lines, at partially suppressing the defects resulting from mutations in their cognate mt‐tRNAs. We now show that leucyl tRNA synthetase is able to partially rescue defects caused by mutations in non‐cognate mt‐tRNAs. Further, a C terminal peptide alone can enter mitochondria and interact with the same spectrum of mt‐tRNAs as the entire synthetase, in intact cells. These data support the possibility that a small peptide could correct at least the biochemical defect associated with many mt‐tRNA mutations, inferring a novel therapy for these disorders. Synopsis A non‐cognate mitochondrial aminoacyl tRNA synthetase can overcome the respiratory defect caused by an mt‐tRNA mutation. The pathogenic mutation can be suppressed by a short peptide corresponding to the C‐terminus of leucyl tRNA synthetase. Human mitochondrial leucyl tRNA synthetase (LARS2) can bind many species of mt‐tRNAs, not exclusively mt‐tRNAleu(UUR) or mt‐tRNAleu(CUN) Binding can stabilize mt‐tRNAs that carry pathogenic destabilizing mutations such as that generated from the m.1624C>T in the gene encoding mt‐tRNAVal A C‐terminal peptide of LARS2 is able to access the mitochondrial matrix and bind a similar spectrum of mt‐tRNAs to the complete LARS2 protein This short peptide has potential to be a therapeutic molecule for many pathogenic mt‐tRNA mutations. Graphical Abstract A non‐cognate mitochondrial aminoacyl tRNA synthetase can overcome the respiratory defect caused by an mt‐tRNA mutation. The pathogenic mutation can be suppressed by a short peptide corresponding to the C‐terminus of leucyl tRNA synthetase.