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Mitochondrial Aminoacyl-tRNA Synthetases

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Mitochondrial Disorders Caused by Nuclear Genes

Abstract

Aminoacyl-tRNA synthetases are an ancient family of enzymes that are essential in determining and accurately maintaining the genetic code. In the initial step of protein synthesis, the aminoacylation process requires each synthetase to specifically recognize and bind its cognate tRNA and to catalyze the transfer of the appropriate amino acid to the acceptor stem of the tRNA. The aminoacylation in the cytoplasm and mitochondria is largely performed by distinct sets of synthetases, which are encoded by separate nuclear genes. This separation is thought to be the consequence of evolutionary pressure of mitochondrial DNA size reduction, which has resulted in truncated tRNAs and subsequent inability of cytoplasmic aminoacyl-tRNA synthetases to recognize the mitochondrial tRNAs. Two enzymes, glycyl-and lysyl-tRNA synthetase, are exceptions because the same nuclear genes (GARS and KARS, respectively) encode both the cytoplasmic and the mitochondrial protein.

Patients with autosomal-recessive mutations in six genes (DARS2, RARS2, YARS2, SARS2, HARS2, and AARS2) encoding mitochondrial aminoacyl-tRNA synthetases have recently been reported, making this group of enzymes a new important cause of protein synthesis defects in the mitochondria. In addition, dominant mutations in GARS and KARS underlie Charcot-Marie-Tooth neuropathy. Deficient mitochondrial translation could be expected to reduce OXPHOS capacity and lead to ATP-deficiency in all tissues, primarily affecting the high-energy demanding tissues such as brain, heart, and skeletal muscle. Surprisingly, however, the defects in mitochondrial aminoacyl-tRNA synthetases have been identified in different types of tissue-specific disorders. The mechanism for the tissue-specificity is not currently understood.

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Authors and Affiliations

  1. Research Program of Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, 00014, Helsinki, Finland

    Henna Tyynismaa

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  1. Henna Tyynismaa
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Correspondence to Henna Tyynismaa .

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  1. , Dept. of Molecular and Human Genetics, Baylor College of Medicine, Baylor Plaza ONE, Houston, 77030, Texas, USA

    Lee-Jun C. Wong

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Tyynismaa, H. (2013). Mitochondrial Aminoacyl-tRNA Synthetases. In: Wong, LJ. (eds) Mitochondrial Disorders Caused by Nuclear Genes. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3722-2_16

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