Distinct pre-initiation steps in human mitochondrial translation

Khawaja, Anas; Itoh, Yuzuru; Remes, Cristina; Spåhr, Henrik; Yukhnovets, Olessya; Höfig, Henning; Amunts, Alexey; Rorbach, Joanna

doi:10.1038/s41467-020-16503-2

Cited by 56 publications

(72 citation statements)

References 30 publications

(37 reference statements)

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“…The reason for the accumulation of these SSU/mt-IF3 complexes is unclear, but it could reflect a relatively low level of translation initiation in T. cruzi , at least at the growth stage at which the parasites were harvested. This complex is also somewhat different from that observed in humans, where mt-IF3 does not contact uS12m and a N-terminal extension contacts uS7m and mS37 ( 28 , 29 ), which was not observed here ( SI Appendix , Fig. S5 E ).…”

Section: Discussioncontrasting

confidence: 91%

Structure of the mature kinetoplastids mitoribosome and insights into its large subunit biogenesis

Soufari

Waltz

Parrot

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Kinetoplastids are unicellular eukaryotic parasites responsible for such human pathologies as Chagas disease, sleeping sickness, and leishmaniasis. They have a single large mitochondrion, essential for the parasite survival. In kinetoplastid mitochondria, most of the molecular machineries and gene expression processes have significantly diverged and specialized, with an extreme example being their mitochondrial ribosomes. These large complexes are in charge of translating the few essential mRNAs encoded by mitochondrial genomes. Structural studies performed inTrypanosoma bruceialready highlighted the numerous peculiarities of these mitoribosomes and the maturation of their small subunit. However, several important aspects mainly related to the large subunit (LSU) remain elusive, such as the structure and maturation of its ribosomal RNA. Here we present a cryo-electron microscopy study of the protozoansLeishmania tarentolaeandTrypanosoma cruzimitoribosomes. For both species, we obtained the structure of their mature mitoribosomes, complete rRNA of the LSU, as well as previously unidentified ribosomal proteins. In addition, we introduce the structure of an LSU assembly intermediate in the presence of 16 identified maturation factors. These maturation factors act on both the intersubunit and the solvent sides of the LSU, where they refold and chemically modify the rRNA and prevent early translation before full maturation of the LSU.

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Section: Discussioncontrasting

confidence: 91%

Structure of the mature kinetoplastids mitoribosome and insights into its large subunit biogenesis

Soufari

Waltz

Parrot

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Progress has been made in obtaining structural data on the mitoribosomes from porcine tissues ( Greber et al, 2014 ; Greber et al, 2015 ), HEK293S-derived cells ( Brown et al, 2014 ; Amunts et al, 2015 ; Brown et al, 2017 ), and initiation complexes have been reconstituted ( Kummer et al, 2018 ; Khawaja et al, 2020 ). While these data yielded the first snapshots, the available structural models are incomplete with key components responsible for mt-mRNA and mt-tRNA binding missing, which reflects the dynamic nature of translation.…”

Section: Introductionmentioning

confidence: 99%

Structural basis of mitochondrial translation

Aibara

Singh

Modelska

et al. 2020

eLife

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119

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Translation of mitochondrial messenger RNA (mt-mRNA) is performed by distinct mitoribosomes comprising at least 36 mitochondria-specific proteins. How these mitoribosomal proteins assist in the binding of mt-mRNA and to what extent they are involved in the translocation of transfer RNA (mt-tRNA) is unclear. To visualize the process of translation in human mitochondria, we report ~3.0 Å resolution structure of the human mitoribosome, including the L7/L12 stalk, and eight structures of its functional complexes with mt-mRNA, mt-tRNAs, recycling factor and additional trans factors. The study reveals a transacting protein module LRPPRC-SLIRP that delivers mt-mRNA to the mitoribosomal small subunit through a dedicated platform formed by the mitochondria-specific protein mS39. Mitoribosomal proteins of the large subunit mL40, mL48, and mL64 coordinate translocation of mt-tRNA. The comparison between those structures shows dynamic interactions between the mitoribosome and its ligands, suggesting a sequential mechanism of conformational changes.

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“…Our preliminary analysis of the already available high-resolution maps of mt-SSU ( Khawaja et al, 2020 ) allowed us to identify densities corresponding to all five methylations of the 12S rRNA ( Figure 2 ), proving that cryoEM is indeed a great tool to investigate mt-rRNA modifications. There is no doubt that the same will be achieved soon for 16S rRNA and can be expanded to mitoribosomes isolated from different tissues, thanks to the continuous improvements in cryoEM methodology.…”

Section: Future Prospects: Emerging Technologies To Investigate Rrna mentioning

confidence: 83%

Methylation of Ribosomal RNA: A Mitochondrial Perspective

et al. 2020

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Ribosomal RNA (rRNA) from all organisms undergoes post-transcriptional modifications that increase the diversity of its composition and activity. In mitochondria, specialized mitochondrial ribosomes (mitoribosomes) are responsible for the synthesis of 13 oxidative phosphorylation proteins encoded by the mitochondrial genome. Mitoribosomal RNA is also modified, with 10 modifications thus far identified and all corresponding modifying enzymes described. This form of epigenetic regulation of mitochondrial gene expression affects mitoribosome biogenesis and function. Here, we provide an overview on rRNA methylation and highlight critical work that is beginning to elucidate its role in mitochondrial gene expression. Given the similarities between bacterial and mitochondrial ribosomes, we focus on studies involving Escherichia coli and human models. Furthermore, we highlight the use of state-of-the-art technologies, such as cryoEM in the study of rRNA methylation and its biological relevance. Understanding the mechanisms and functional relevance of this process represents an exciting frontier in the RNA biology and mitochondrial fields.

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Distinct pre-initiation steps in human mitochondrial translation

Cited by 56 publications

References 30 publications

Structure of the mature kinetoplastids mitoribosome and insights into its large subunit biogenesis

Structure of the mature kinetoplastids mitoribosome and insights into its large subunit biogenesis

Structural basis of mitochondrial translation

Methylation of Ribosomal RNA: A Mitochondrial Perspective

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