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J Biol Chem. 2018 Aug 31;293(35):13604-13615. doi: 10.1074/jbc.RA118.003400. Epub 2018 Jul 13.

Three human aminoacyl-tRNA synthetases have distinct sub-mitochondrial localizations that are unaffected by disease-associated mutations.

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From the Université de Strasbourg, CNRS, Architecture et Réactivité de l'ARN, UPR9002, F-67084 Strasbourg, France and.
the INSERM UMR 1163, Laboratory of Genetics of Mitochondrial Disorders, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, F-75015 Paris, France.
From the Université de Strasbourg, CNRS, Architecture et Réactivité de l'ARN, UPR9002, F-67084 Strasbourg, France and


Human mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are key enzymes in the mitochondrial protein translation system and catalyze the charging of amino acids on their cognate tRNAs. Mutations in their nuclear genes are associated with pathologies having a broad spectrum of clinical phenotypes, but with no clear molecular mechanism(s). For example, mutations in the nuclear genes encoding mt-AspRS and mt-ArgRS are correlated with the moderate neurodegenerative disorder leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) and with the severe neurodevelopmental disorder pontocerebellar hypoplasia type 6 (PCH6), respectively. Previous studies have shown no or only minor impacts of these mutations on the canonical properties of these enzymes, indicating that the role of the mt-aaRSs in protein synthesis is mostly not affected by these mutations, but their effects on the mitochondrial localizations of aaRSs remain unclear. Here, we demonstrate that three human aaRSs, mt-AspRS, mt-ArgRS, and LysRS, each have a specific sub-mitochondrial distribution, with mt-ArgRS being exclusively localized in the membrane, LysRS exclusively in the soluble fraction, and mt-AspRS being present in both. Chemical treatments revealed that mt-AspRs is anchored in the mitochondrial membrane through electrostatic interactions, whereas mt-ArgRS uses hydrophobic interactions. We also report that novel mutations in mt-AspRS and mt-ArgRS genes from individuals with LBSL and PCH6, respectively, had no significant impact on the mitochondrial localizations of mt-AspRS and mt-ArgRS. The variable sub-mitochondrial locations for these three mt-aaRSs strongly suggest the existence of additional enzyme properties, requiring further investigation to unravel the mechanisms underlying the two neurodegenerative disorders.


aminoacyl tRNA synthetase; dual-localization; human; leukodystrophy; membrane-anchored; mitochondria; mitochondrial disorder; neurodegenerative disease; pontocerebellar hypoplasia; translation

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