Translation in Mammalian Mitochondria: Order and Disorder Linked to tRNAs and Aminoacyl-tRNA Synthetases

Florentz, Catherine; Pütz, Joern; Jühling, Frank; Schwenzer, Hagen; Stadler, Peter F.; Lorber, Bernard; Sauter, Claude

doi:10.1007/978-3-642-39426-3_3

Cited by 2 publications

(4 citation statements)

References 115 publications

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“…The pathogenic mechanisms behind the tissue-specific manifestations are likely to involve cell type-specific mitochondrial functions and metabolite requirements, in addition to defects of ATP production by oxidative phosphorylation ( Nunnari and Suomalainen, 2012 ). 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 ). The example of AARS2 , however, shows that mutations in the same mtARS can also give rise to highly different tissue-specific diseases.…”

Section: Discussionmentioning

confidence: 99%

Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation

et al. 2015

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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.

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Section: Discussionmentioning

confidence: 99%

Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation

et al. 2015

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“…Identity elements of mitochondrial tRNAs have been analyzed in-vitro for trnR ( 14 ), trnD ( 15 ), trnY ( 15 , 16 ), trnL ( 17 ), trnS ( 18 , 19 ) and trnA ( 20 ). For the remaining tRNAs, identity elements have been analyzed in-silico through sequence and structural conservation studies, and comparisons to known identity elements of Escherichia coli ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

“… Only a reduced set of identity elements for the aminoacylation of mitochondrial tRNAs exists, i.e. for most tRNAs the anticodon is the main identity element ( 15 , 21 ). The simplification of the translation machinery has left only a single tRNA for each amino acid (except for trnL and trnS ).…”

Section: Introductionmentioning

confidence: 99%

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Towards a comprehensive picture of alloacceptor tRNA remolding in metazoan mitochondrial genomes

et al. 2015

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Remolding of tRNAs is a well-documented process in mitochondrial genomes that changes the identity of a tRNA. It involves a duplication of a tRNA gene, a mutation that changes the anticodon and the loss of the ancestral tRNA gene. The net effect is a functional tRNA that is more closely related to tRNAs of a different alloacceptor family than to tRNAs with the same anticodon in related species. Beyond being of interest for understanding mitochondrial tRNA function and evolution, tRNA remolding events can lead to artifacts in the annotation of mitogenomes and thus in studies of mitogenomic evolution. Therefore, it is important to identify and catalog these events. Here we describe novel methods to detect tRNA remolding in large-scale data sets and apply them to survey tRNA remolding throughout animal evolution. We identify several novel remolding events in addition to the ones previously mentioned in the literature. A detailed analysis of these remoldings showed that many of them are derived from ancestral events.

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Translation in Mammalian Mitochondria: Order and Disorder Linked to tRNAs and Aminoacyl-tRNA Synthetases

Cited by 2 publications

References 115 publications

Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation

Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation

Towards a comprehensive picture of alloacceptor tRNA remolding in metazoan mitochondrial genomes

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