B Martin Hällberg and Nils-Göran Larsson; Cell Metabolism (5 August 2014)
This review discusses the elements of mitochondrial transcription and translation, and the pathogenic effects of defects.
Mitochondrial DNA contains essential subunits of proteins involved in the oxidative phosphorylation system, as well as the tRNA and rRNA required for translation of proteins inside the mitochondrion. Although the vast majority of mitochondrial proteins are imported, failure to correctly translate the proteins encoded by mtDNA can lead to defects in oxidative phosphorylation, which can lead to significant negative consequences for the organism. Such a failure can occur either through mutation of a gene encoding a protein, or through damage to tRNA or rRNA impairing the mitochondrial translation system as a whole. The authors give the example of two mutations in the 12S rRNA gene of mitochondria which can lead to deafness, as well as referencing a subset of mtDNA mutations found in aging which can impair mitochondrial translation.
mtDNA transcription by mitochondrial RNA polymerase (POLRMT) leads to the creation of two long transcripts, one from each strand. These are punctuated by tRNA which are then cleaved at their 5' and 3' ends to release the mRNA strands held between them. It is currently unclear how mRNAs which are not between two tRNAs are released and processed. Early transcript processing is believed to take place alongside transcription in mitochondrial RNA granules, which may be followed by a second round of processing outside of these granules. Mitochondria possess a specific polyA polymerase (mtPAP) which performs polyadenylation of mitochondrial mRNA; without this polyadenylation mitochondrial mRNA stability is impaired and translation decreases.
Mammalian tRNAs are inherently less stable than other types of tRNA due to structural differences. The authors state that this makes them more susceptible to processing and modification defects, and that over 100 mutations in mitochondrial tRNAs have been observed to be pathogenic. The aminoacyltransferases responsible for charging mitochondrial tRNAs are all encoded in the nucleus.
Mitochondrial ribosome biogenesis requires the co-ordination of both nuclear and mitochondrial processes; 12S and 16S mitochondrial rRNA must be assembled with ribosomal proteins imported from outside of the mitochondrion. Translating mitoribosomes have been reported to be tethered to the inner mitochondrial membrane. The authors also discuss post-transcriptional modifications of 12S and 16S mitochondrial rRNA and the biogenesis of the mitoribosomal subunits.
The mammalian mitoribosome has a mass ratio of RNA to protein of 1:2, whereas bacterial and eukaryotic cytosolic ribosomes have a ratio of 2:1. The authors suggest that this reflects the loss of rRNA components since absorption of the proteobacterium that formed primitive mitochondria, and the replacement of these components with nuclearly encoded proteins.
The authors discuss the fact that at least one tRNA gene is always lost in all pathogenic single large deletion mutations of human mtDNA and that these mutations always lead to heteroplasmy and a require a heteroplasmy of >60% to impair translation. Heteroplasmic tRNA point mutations are also stated to be common causes of mitochondrial disease. Nuclear mutations affecting genes controlling mitochondrial translation also have a wide variety of potential pathological effects.
Finally, the authors discuss the fact the surprising complexity of the mitochondrial translation given its limited remit, and the number of nuclear-encoded genes that must be coordinated with mitochondrial translation in order to permit correct function. They emphasise the importance of studying mitochondrial translation in order to understand both mitochondrial disease and aging.
Mitochondrial DNA contains essential subunits of proteins involved in the oxidative phosphorylation system, as well as the tRNA and rRNA required for translation of proteins inside the mitochondrion. Although the vast majority of mitochondrial proteins are imported, failure to correctly translate the proteins encoded by mtDNA can lead to defects in oxidative phosphorylation, which can lead to significant negative consequences for the organism. Such a failure can occur either through mutation of a gene encoding a protein, or through damage to tRNA or rRNA impairing the mitochondrial translation system as a whole. The authors give the example of two mutations in the 12S rRNA gene of mitochondria which can lead to deafness, as well as referencing a subset of mtDNA mutations found in aging which can impair mitochondrial translation.
mtDNA transcription by mitochondrial RNA polymerase (POLRMT) leads to the creation of two long transcripts, one from each strand. These are punctuated by tRNA which are then cleaved at their 5' and 3' ends to release the mRNA strands held between them. It is currently unclear how mRNAs which are not between two tRNAs are released and processed. Early transcript processing is believed to take place alongside transcription in mitochondrial RNA granules, which may be followed by a second round of processing outside of these granules. Mitochondria possess a specific polyA polymerase (mtPAP) which performs polyadenylation of mitochondrial mRNA; without this polyadenylation mitochondrial mRNA stability is impaired and translation decreases.
Mammalian tRNAs are inherently less stable than other types of tRNA due to structural differences. The authors state that this makes them more susceptible to processing and modification defects, and that over 100 mutations in mitochondrial tRNAs have been observed to be pathogenic. The aminoacyltransferases responsible for charging mitochondrial tRNAs are all encoded in the nucleus.
Mitochondrial ribosome biogenesis requires the co-ordination of both nuclear and mitochondrial processes; 12S and 16S mitochondrial rRNA must be assembled with ribosomal proteins imported from outside of the mitochondrion. Translating mitoribosomes have been reported to be tethered to the inner mitochondrial membrane. The authors also discuss post-transcriptional modifications of 12S and 16S mitochondrial rRNA and the biogenesis of the mitoribosomal subunits.
The mammalian mitoribosome has a mass ratio of RNA to protein of 1:2, whereas bacterial and eukaryotic cytosolic ribosomes have a ratio of 2:1. The authors suggest that this reflects the loss of rRNA components since absorption of the proteobacterium that formed primitive mitochondria, and the replacement of these components with nuclearly encoded proteins.
The authors discuss the fact that at least one tRNA gene is always lost in all pathogenic single large deletion mutations of human mtDNA and that these mutations always lead to heteroplasmy and a require a heteroplasmy of >60% to impair translation. Heteroplasmic tRNA point mutations are also stated to be common causes of mitochondrial disease. Nuclear mutations affecting genes controlling mitochondrial translation also have a wide variety of potential pathological effects.
Finally, the authors discuss the fact the surprising complexity of the mitochondrial translation given its limited remit, and the number of nuclear-encoded genes that must be coordinated with mitochondrial translation in order to permit correct function. They emphasise the importance of studying mitochondrial translation in order to understand both mitochondrial disease and aging.
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