bims-mitran 2021-07-25 papers

bims-mitran

Biomed News

on Mitochondrial Translation

Issue of 2021–07–25
seven papers selected by
Andreas Kohler, Stockholm University

Mitochondrial Protein Translation: Emerging Roles and Clinical Significance in Disease.
Accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in Huntington's disease.
Case Report: Mitochondrial Encephalomyopathy Presents as Epilepsy, Ataxia, and Dystonia With a Rare Mutation in MT-TW.
AP sites in various mRNA positions cross-link to the protein uS3 in the translating mammalian ribosome.
Saccharomyces cerevisiae, a Powerful Model for Studying rRNA Modifications and Their Effects on Translation Fidelity.
Structural and mechanistic basis for translation inhibition by macrolide and ketolide antibiotics.
Ribosome heterogeneity in Drosophila melanogaster gonads through paralog-switching.

Front Cell Dev Biol. 2021 ;9 675465

Mitochondrial Protein Translation: Emerging Roles and Clinical Significance in Disease.

Fei Wang, Deyu Zhang, Dejiu Zhang, Peifeng Li, Yanyan Gao.

  Mitochondria are one of the most important organelles in cells. Mitochondria are semi-autonomous organelles with their own genetic system, and can independently replicate, transcribe, and translate mitochondrial DNA. Translation initiation, elongation, termination, and recycling of the ribosome are four stages in the process of mitochondrial protein translation. In this process, mitochondrial protein translation factors and translation activators, mitochondrial RNA, and other regulatory factors regulate mitochondrial protein translation. Mitochondrial protein translation abnormalities are associated with a variety of diseases, including cancer, cardiovascular diseases, and nervous system diseases. Mutation or deletion of various mitochondrial protein translation factors and translation activators leads to abnormal mitochondrial protein translation. Mitochondrial tRNAs and mitochondrial ribosomal proteins are essential players during translation and mutations in genes encoding them represent a large fraction of mitochondrial diseases. Moreover, there is crosstalk between mitochondrial protein translation and cytoplasmic translation, and the imbalance between mitochondrial protein translation and cytoplasmic translation can affect some physiological and pathological processes. This review summarizes the regulation of mitochondrial protein translation factors, mitochondrial ribosomal proteins, mitochondrial tRNAs, and mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) in the mitochondrial protein translation process and its relationship with diseases. The regulation of mitochondrial protein translation and cytoplasmic translation in multiple diseases is also summarized.

Keywords:  cytoplasmic translation; mitochondria; mitochondrial aminoacyl-tRNA synthetase; mitochondrial ribosome; mitoribosome assembly factors; protein translation; translation activators; translation factors

DOI:  https://doi.org/10.3389/fcell.2021.675465
Proc Natl Acad Sci U S A. 2021 Jul 27. pii: e2014610118. [Epub ahead of print]118(30):

Accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in Huntington's disease.

Yiqin Wang, Xiaoxian Guo, Kaixiong Ye, Michael Orth, Zhenglong Gu.

  Mitochondrial dysfunction is found in the brain and peripheral tissues of patients diagnosed with Huntington's disease (HD), an irreversible neurodegenerative disease of which aging is a major risk factor. Mitochondrial function is encoded by not only nuclear DNA but also DNA within mitochondria (mtDNA). Expansion of mtDNA heteroplasmies (coexistence of mutated and wild-type mtDNA) can contribute to age-related decline of mitochondrial function but has not been systematically investigated in HD. Here, by using a sensitive mtDNA-targeted sequencing method, we studied mtDNA heteroplasmies in lymphoblasts and longitudinal blood samples of HD patients. We found a significant increase in the fraction of mtDNA heteroplasmies with predicted pathogenicity in lymphoblasts from 1,549 HD patients relative to lymphoblasts from 182 healthy individuals. The increased fraction of pathogenic mtDNA heteroplasmies in HD lymphoblasts also correlated with advancing HD stages and worsened disease severity measured by HD motor function, cognitive function, and functional capacity. Of note, elongated CAG repeats in HTT promoted age-dependent expansion of pathogenic mtDNA heteroplasmies in HD lymphoblasts. We then confirmed in longitudinal blood samples of 169 HD patients that expansion of pathogenic mtDNA heteroplasmies was correlated with decline in functional capacity and exacerbation of HD motor and cognitive functions during a median follow-up of 6 y. The results of our study indicate accelerated decline of mtDNA quality in HD, and highlight monitoring mtDNA heteroplasmies longitudinally as a way to investigate the progressive decline of mitochondrial function in aging and age-related diseases.

Keywords:  Huntington’s disease; mitochondrial DNA; sequencing

DOI:  https://doi.org/10.1073/pnas.2014610118
Front Neurol. 2021 ;12 679302

Case Report: Mitochondrial Encephalomyopathy Presents as Epilepsy, Ataxia, and Dystonia With a Rare Mutation in MT-TW.

Shuang Wang, Jing Miao, Jiachun Feng.

  Mitochondrial diseases are a group of common inherited disorders caused by mutations in nuclear DNA or mitochondrial DNA (mtDNA); the clinical phenotype of diseases caused by mutant mtDNA is challenging owing to heteroplasmy of mtDNA and may delay diagnosis and treatment. Herein, we report the case of an adult male who slowly developed epilepsy, ataxia, dystonia, impaired cognition, and hearing impairment over 14 years in the absence of clinical myopathy. His lactate level was normal. Brain computed tomography showed calcifications of the bilateral basal ganglia, thalamus, and cerebellar dentate nuclei. Magnetic resonance imaging revealed multiple lesions in the bilateral internal capsule and periventricular areas, which were hypointense on T1-weighted images and hyperintense on T2-weighted images. The first blood genetic test result was negative. Two years later, a muscle biopsy was performed. Succinate dehydrogenase (SDH) staining showed several ragged blue fibers and atypical strongly SDH-reactive vessels. Cytochrome C oxidase (COX) staining revealed abundant COX-deficient fibers. mtDNA testing of blood and muscle revealed a rare m.5549G>A mutation in the MT-TW gene. It was heteroplasmic, with 5.4% mutant mtDNA in the blood and 61.5% in the muscle. The patient was diagnosed with mitochondrial encephalomyopathy and treated with levetiracetam instead of valproate to reduce possible mitochondrial toxicity. After receiving anti-epileptic drugs and mitochondrial supplements, the patient remained clinically stable. For mitochondrial disease, when mutant mtDNA is not detected in blood, muscle biopsy should be performed in routine analysis, and it should be genetically tested, even if there are no manifestations of myopathy.

Keywords:  MT-TW; ataxia; dystonia; epilepsy; mitochondrial encephalomyopathy

DOI:  https://doi.org/10.3389/fneur.2021.679302
Biochim Biophys Acta Proteins Proteom. 2021 Jul 14. pii: S1570-9639(21)00104-7. [Epub ahead of print]1869(10): 140698

AP sites in various mRNA positions cross-link to the protein uS3 in the translating mammalian ribosome.

Anastasia S Ochkasova, Maria I Meschaninova, Aliya G Venyaminova, Dmitri M Graifer, Galina G Karpova.

  Abasic (AP) sites in mRNAs are lesions whose accumulation in cells is linked to various neurodegenerative diseases arising from the appearance of truncated peptides due to the premature cessation of translation of these mRNAs. It is believed that the translation of AP site-containing mRNAs is stopped when the damaged codon arrives to the A site, where it is not decoded. We propose an alternative translation arrest mechanism mediated by the 40S ribosomal subunit protein uS3. Recently, it has been shown that in human 80S ribosomal complexes assembled without translation factors, uS3 cross-links to the AP site at the 3'-terminus of the mRNA, whose undamaged part is bound at the 40S subunit channel, via its peptide 55-64 exposed near the mRNA entry pore. In this study, we examined whether such cross-linking occurs during the translation of mRNA with the AP site. To this end, we used a set of synthetic mRNAs bearing the AP site inserted in the desired location in their sequences. An analysis of 80S ribosomal complexes formed with these mRNAs in a mammalian cell-free protein-synthesizing system demonstrates that AP sites do indeed cross-link to uS3 in the course of the translation. We also show that the cross-linking occurs as soon as the AP site arrives to a common favorable position relative to uS3, which is independent on its location in the mRNA. Our findings suggest that the mechanism of stopping translation of damaged mRNAs involving uS3, along with the one mentioned above, could underlie ribosome-associated mRNA quality control.

Keywords:  Abasic (AP) site; Cross-linking; Human ribosome; Ribosomal protein uS3; Ribosome-associated mRNA quality control; Synthetic mRNA analogues; mRNA surveillance

DOI:  https://doi.org/10.1016/j.bbapap.2021.140698
Int J Mol Sci. 2021 Jul 10. pii: 7419. [Epub ahead of print]22(14):

Saccharomyces cerevisiae, a Powerful Model for Studying rRNA Modifications and Their Effects on Translation Fidelity.

Agnès Baudin-Baillieu, Olivier Namy.

  Ribosomal RNA is a major component of the ribosome. This RNA plays a crucial role in ribosome functioning by ensuring the formation of the peptide bond between amino acids and the accurate decoding of the genetic code. The rRNA carries many chemical modifications that participate in its maturation, the formation of the ribosome and its functioning. In this review, we present the different modifications and how they are deposited on the rRNA. We also describe the most recent results showing that the modified positions are not 100% modified, which creates a heterogeneous population of ribosomes. This gave rise to the concept of specialized ribosomes that we discuss. The knowledge accumulated in the yeast Saccharomyces cerevisiae is very helpful to better understand the role of rRNA modifications in humans, especially in ribosomopathies.

Keywords:  RNA modifications; Saccharomyces cerevisiae; ribosomes; translation fidelity

DOI:  https://doi.org/10.3390/ijms22147419
Nat Commun. 2021 07 22. 12(1): 4466

Structural and mechanistic basis for translation inhibition by macrolide and ketolide antibiotics.

Bertrand Beckert, Elodie C Leroy, Shanmugapriya Sothiselvam, Lars V Bock, Maxim S Svetlov, Michael Graf, Stefan Arenz, Maha Abdelshahid, Britta Seip, Helmut Grubmüller, Alexander S Mankin, C Axel Innis, Nora Vázquez-Laslop, Daniel N Wilson.

Macrolides and ketolides comprise a family of clinically important antibiotics that inhibit protein synthesis by binding within the exit tunnel of the bacterial ribosome. While these antibiotics are known to interrupt translation at specific sequence motifs, with ketolides predominantly stalling at Arg/Lys-X-Arg/Lys motifs and macrolides displaying a broader specificity, a structural basis for their context-specific action has been lacking. Here, we present structures of ribosomes arrested during the synthesis of an Arg-Leu-Arg sequence by the macrolide erythromycin (ERY) and the ketolide telithromycin (TEL). Together with deep mutagenesis and molecular dynamics simulations, the structures reveal how ERY and TEL interplay with the Arg-Leu-Arg motif to induce translational arrest and illuminate the basis for the less stringent sequence-specific action of ERY over TEL. Because programmed stalling at the Arg/Lys-X-Arg/Lys motifs is used to activate expression of antibiotic resistance genes, our study also provides important insights for future development of improved macrolide antibiotics.

DOI: https://doi.org/10.1038/s41467-021-24674-9
Nucleic Acids Res. 2021 Jul 20. pii: gkab606. [Epub ahead of print]

Ribosome heterogeneity in Drosophila melanogaster gonads through paralog-switching.

Tayah Hopes, Karl Norris, Michaela Agapiou, Charley G P McCarthy, Philip A Lewis, Mary J O'Connell, Juan Fontana, Julie L Aspden.

Ribosomes have long been thought of as homogeneous macromolecular machines, but recent evidence suggests they are heterogeneous and could be specialised to regulate translation. Here, we have characterised ribosomal protein heterogeneity across 4 tissues of Drosophila melanogaster. We find that testes and ovaries contain the most heterogeneous ribosome populations, which occurs through a combination of paralog-enrichment and paralog-switching. We have solved structures of ribosomes purified from in vivo tissues by cryo-EM, revealing differences in precise ribosomal arrangement for testis and ovary 80S ribosomes. Differences in the amino acid composition of paralog pairs and their localisation on the ribosome exterior indicate paralog-switching could alter the ribosome surface, enabling different proteins to regulate translation. One testis-specific paralog-switching pair is also found in humans, suggesting this is a conserved site of ribosome heterogeneity. Overall, this work allows us to propose that mRNA translation might be regulated in the gonads through ribosome heterogeneity, providing a potential means of ribosome specialisation.

DOI: https://doi.org/10.1093/nar/gkab606