Abstract
The accuracy of mitochondrial protein synthesis is dependent on the coordinated action of nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mtARSs) and the mitochondrial DNA-encoded tRNAs. The recent advances in whole-exome sequencing have revealed the importance of the mtARS proteins for mitochondrial pathophysiology since nearly every nuclear gene for mtARS (out of 19) is now recognized as a disease gene for mitochondrial disease. Typically, defects in each mtARS have been identified in one tissue-specific disease, most commonly affecting the brain, or in one syndrome. However, mutations in the AARS2 gene for mitochondrial alanyl-tRNA synthetase (mtAlaRS) have been reported both in patients with infantile-onset cardiomyopathy and in patients with childhood to adulthood-onset leukoencephalopathy. We present here an investigation of the effects of the described mutations on the structure of the synthetase, in an effort to understand the tissue-specific outcomes of the different mutations. The mtAlaRS differs from the other mtARSs because in addition to the aminoacylation domain, it has a conserved editing domain for deacylating tRNAs that have been mischarged with incorrect amino acids. We show that the cardiomyopathy phenotype results from a single allele, causing an amino acid change R592W in the editing domain of AARS2, whereas the leukodystrophy mutations are located in other domains of the synthetase. Nevertheless, our structural analysis predicts that all mutations reduce the aminoacylation activity of the synthetase, because all mtAlaRS domains contribute to tRNA binding for aminoacylation. According to our model, the cardiomyopathy mutations severely compromise aminoacylation whereas partial activity is retained by the mutation combinations found in the leukodystrophy patients. These predictions provide a hypothesis for the molecular basis of the distinct tissue-specific phenotypic outcomes.
Highlights
Mitochondrial protein synthesis produces key subunits of the oxidative phosphorylation (OXPHOS) complexes that generate the majority of the ATP for our cells
The accuracy of mitochondrial protein synthesis is dependent on the coordinated action of nuclear-encoded mitochondrial aminoacyl-tRNA synthetases and the mitochondrial DNA-encoded tRNAs.The recent advances in whole-exome sequencing have revealed the importance of the mtARS proteins for mitochondrial pathophysiology since nearly every nuclear gene for mtARS is recognized as a disease gene for mitochondrial disease
Differential basal mRNA expression levels of mtARSs have been suggested to contribute to the tissue-specificity, as brain, muscle, and heart were found to have low levels of mtARS mRNAs compared to other tissues (Florentz et al, 2013)
Summary
Mitochondrial protein synthesis produces key subunits of the oxidative phosphorylation (OXPHOS) complexes that generate the majority of the ATP for our cells. Among the necessary proteins are the aminoacyl-tRNA synthetases (ARSs) that recognize specific tRNAs and charge them with cognate amino acids, contributing to the initiation and accuracy of the protein synthesis. Since 2007, the mtARS genes have been recognized as a new group of disease genes affecting mitochondrial protein synthesis (Konovalova and Tyynismaa, 2013; Diodato et al, 2014a; Schwenzer et al, 2014). Proteins need to be synthesized in mitochondria in all cell types, with the exception of red blood cells, and the tissue-specificity of the phenotypes caused by mutations in the different mtARS genes has been unexpected. That pathogenic mutations have been reported in 15 genes encoding mtARSs (and in the two genes GARS and KARS encoding dual localized synthetases for cytoplasmic and mitochondrial translation), we can, conclude that the majority of the mtARS defects affect the central nervous system. The range of CNS phenotypes is remarkably wide, affecting specific neurons in many cases, and including patients with infantile-, earlyand late-onset of disease
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