Mitochondrial (mt) diseases are multisystem disorders due to mutations in nuclear or mtDNA genes. Among the latter, more than 50% are located in transfer RNA (tRNA) genes and are responsible for a wide range of syndromes, for which no effective treatment is available at present. We show that three human mt aminoacyl-tRNA syntethases, namely leucyl-, valyl-, and isoleucyl-tRNA synthetase are able to improve both viability and bioenergetic proficiency of human transmitochondrial cybrid cells carrying pathogenic mutations in the mt-tRNAIle gene. Importantly, we further demonstrate that the carboxy-terminal domain of human mt leucyl-tRNA synthetase is both necessary and sufficient to improve the pathologic phenotype associated either with these “mild” mutations or with the “severe” m.3243A>G mutation in the mt-tRNALeu(UUR) gene. Furthermore, we provide evidence that this small, non-catalytic domain is able to directly and specifically interact in vitro with human mt-tRNALeu(UUR) with high affinity and stability and, with lower affinity, with mt-tRNAIle. Taken together, our results sustain the hypothesis that the carboxy-terminal domain of human mt leucyl-tRNA synthetase can be used to correct mt dysfunctions caused by mt-tRNA mutations.
Non-cognate mitochondrial aminoacyl-tRNA syntethases improve viability and bionergetic proficiency of human cells with pathogenic mutations in the mt-tRNAIle gene. The isolated carboxy-terminal domain of human mt-leucyl tRNA synthetase improves the pathologic phenotype.
- Mitochondrial aminoacyl-tRNA syntethases (mt-aaRSs) can rescue the pathologic phenotype of human cells carrying mutations, both in cognate and non-cognate mitochondrial tRNAs.
- The carboxy-terminal domain of mt-leucyl syntethase (mt-LeuRS Cterm) is sufficient to exert the rescuing effect, even more efficiently than the whole enzyme.
- In line with its rescuing effect, mt-LeuRS Cterm is imported within mitochondria, even in absence of a canonical mt import sequence.