bims-tricox Biomed News
on Translation, ribosomes and COX
Issue of 2022‒10‒30
six papers selected by
Yash Verma
University of Delhi South Campus
  1. Are there roles for heterogeneous ribosomes during sleep in the rodent brain?
  2. The mystery of massive mitochondrial complexes: the apicomplexan respiratory chain.
  3. The role of GTP hydrolysis by EF-G in ribosomal translocation.
  4. Profiling subcellular localization of nuclear-encoded mitochondrial gene products in zebrafish.
  5. Human mtRF1 terminates COX1 translation and its ablation induces mitochondrial ribosome-associated quality control.
  6. Miro GTPase domains regulate the assembly of the mitochondrial motor-adaptor complex.
  1. Front Mol Biosci. 2022 ;9 1008921
    Are there roles for heterogeneous ribosomes during sleep in the rodent brain?
    Isla M Buchanan, Trevor M Smith, André P Gerber, Julie Seibt.
      The regulation of mRNA translation plays an essential role in neurons, contributing to important brain functions, such as brain plasticity and memory formation. Translation is conducted by ribosomes, which at their core consist of ribosomal proteins (RPs) and ribosomal RNAs. While translation can be regulated at diverse levels through global or mRNA-specific means, recent evidence suggests that ribosomes with distinct configurations are involved in the translation of different subsets of mRNAs. However, whether and how such proclaimed ribosome heterogeneity could be connected to neuronal functions remains largely unresolved. Here, we postulate that the existence of heterologous ribosomes within neurons, especially at discrete synapses, subserve brain plasticity. This hypothesis is supported by recent studies in rodents showing that heterogeneous RP expression occurs in dendrites, the compartment of neurons where synapses are made. We further propose that sleep, which is fundamental for brain plasticity and memory formation, has a particular role in the formation of heterologous ribosomes, specialised in the translation of mRNAs specific for synaptic plasticity. This aspect of our hypothesis is supported by recent studies showing increased translation and changes in RP expression during sleep after learning. Thus, certain RPs are regulated by sleep, and could support different sleep functions, in particular brain plasticity. Future experiments investigating cell-specific heterogeneity in RPs across the sleep-wake cycle and in response to different behaviour would help address this question.
    Keywords:  brain plasticity; neurites; neuron; ribosomal protein; ribosome heterogeneity; sleep; synapse
    DOI:  https://doi.org/10.3389/fmolb.2022.1008921
  2. Trends Parasitol. 2022 Oct 24. pii: S1471-4922(22)00219-7. [Epub ahead of print]
    The mystery of massive mitochondrial complexes: the apicomplexan respiratory chain.
    Andrew E Maclean, Jenni A Hayward, Diego Huet, Giel G van Dooren, Lilach Sheiner.
      The mitochondrial respiratory chain is an essential pathway in most studied eukaryotes due to its roles in respiration and other pathways that depend on mitochondrial membrane potential. Apicomplexans are unicellular eukaryotes whose members have an impact on global health. The respiratory chain is a drug target for some members of this group, notably the malaria-causing Plasmodium spp. This has motivated studies of the respiratory chain in apicomplexan parasites, primarily Toxoplasma gondii and Plasmodium spp. for which experimental tools are most advanced. Studies of the respiratory complexes in these organisms revealed numerous novel features, including expansion of complex size. The divergence of apicomplexan mitochondria from commonly studied models highlights the diversity of mitochondrial form and function across eukaryotic life.
    Keywords:  Apicomplexa; F(o)-F(1) ATP synthase; Plasmodium; Toxoplasma; mitochondrial electron transport chain; mitochondrion
    DOI:  https://doi.org/10.1016/j.pt.2022.09.008
  3. Proc Natl Acad Sci U S A. 2022 Nov;119(44): e2212502119
    The role of GTP hydrolysis by EF-G in ribosomal translocation.
    Gillian Rexroad, John Paul Donohue, Laura Lancaster, Harry F Noller.
      Translocation of transfer RNA (tRNA) and messenger RNA (mRNA) through the ribosome is catalyzed by the GTPase elongation factor G (EF-G) in bacteria. Although guanosine-5'-triphosphate (GTP) hydrolysis accelerates translocation and is required for dissociation of EF-G, its fundamental role remains unclear. Here, we used ensemble Förster resonance energy transfer (FRET) to monitor how inhibition of GTP hydrolysis impacts the structural dynamics of the ribosome. We used FRET pairs S12-S19 and S11-S13, which unambiguously report on rotation of the 30S head domain, and the S6-L9 pair, which measures intersubunit rotation. Our results show that, in addition to slowing reverse intersubunit rotation, as shown previously, blocking GTP hydrolysis slows forward head rotation. Surprisingly, blocking GTP hydrolysis completely abolishes reverse head rotation. We find that the S13-L33 FRET pair, which has been used in previous studies to monitor head rotation, appears to report almost exclusively on intersubunit rotation. Furthermore, we find that the signal from quenching of 3'-terminal pyrene-labeled mRNA, which is used extensively to follow mRNA translocation, correlates most closely with reverse intersubunit rotation. To account for our finding that blocking GTP hydrolysis abolishes a rotational event that occurs after the movements of mRNA and tRNAs are essentially complete, we propose that the primary role of GTP hydrolysis is to create an irreversible step in a mechanism that prevents release of EF-G until both the tRNAs and mRNA have moved by one full codon, ensuring productive translocation and maintenance of the translational reading frame.
    Keywords:  FRET; frameshifting; ribosome; translation
    DOI:  https://doi.org/10.1073/pnas.2212502119
  4. Life Sci Alliance. 2023 Jan;pii: e202201514. [Epub ahead of print]6(1):
    Profiling subcellular localization of nuclear-encoded mitochondrial gene products in zebrafish.
    Barbara Uszczynska-Ratajczak, Sreedevi Sugunan, Monika Kwiatkowska, Maciej Migdal, Silvia Carbonell-Sala, Anna Sokol, Cecilia L Winata, Agnieszka Chacinska.
      Most mitochondrial proteins are encoded by nuclear genes, synthetized in the cytosol and targeted into the organelle. To characterize the spatial organization of mitochondrial gene products in zebrafish (Danio rerio), we sequenced RNA from different cellular fractions. Our results confirmed the presence of nuclear-encoded mRNAs in the mitochondrial fraction, which in unperturbed conditions, are mainly transcripts encoding large proteins with specific properties, like transmembrane domains. To further explore the principles of mitochondrial protein compartmentalization in zebrafish, we quantified the transcriptomic changes for each subcellular fraction triggered by the chchd4a -/- mutation, causing the disorders in the mitochondrial protein import. Our results indicate that the proteostatic stress further restricts the population of transcripts on the mitochondrial surface, allowing only the largest and the most evolutionary conserved proteins to be synthetized there. We also show that many nuclear-encoded mitochondrial transcripts translated by the cytosolic ribosomes stay resistant to the global translation shutdown. Thus, vertebrates, in contrast to yeast, are not likely to use localized translation to facilitate synthesis of mitochondrial proteins under proteostatic stress conditions.
    DOI:  https://doi.org/10.26508/lsa.202201514
  5. Nat Commun. 2022 Oct 27. 13(1): 6406
    Human mtRF1 terminates COX1 translation and its ablation induces mitochondrial ribosome-associated quality control.
    Franziska Nadler, Elena Lavdovskaia, Angelique Krempler, Luis Daniel Cruz-Zaragoza, Sven Dennerlein, Ricarda Richter-Dennerlein.
      Translation termination requires release factors that read a STOP codon in the decoding center and subsequently facilitate the hydrolysis of the nascent peptide chain from the peptidyl tRNA within the ribosome. In human mitochondria eleven open reading frames terminate in the standard UAA or UAG STOP codon, which can be recognized by mtRF1a, the proposed major mitochondrial release factor. However, two transcripts encoding for COX1 and ND6 terminate in the non-conventional AGA or AGG codon, respectively. How translation termination is achieved in these two cases is not known. We address this long-standing open question by showing that the non-canonical release factor mtRF1 is a specialized release factor that triggers COX1 translation termination, while mtRF1a terminates the majority of other mitochondrial translation events including the non-canonical ND6. Loss of mtRF1 leads to isolated COX deficiency and activates the mitochondrial ribosome-associated quality control accompanied by the degradation of COX1 mRNA to prevent an overload of the ribosome rescue system. Taken together, these results establish the role of mtRF1 in mitochondrial translation, which had been a mystery for decades, and lead to a comprehensive picture of translation termination in human mitochondria.
    DOI:  https://doi.org/10.1038/s41467-022-34088-w
  6. Life Sci Alliance. 2023 Jan;pii: e202201406. [Epub ahead of print]6(1):
    Miro GTPase domains regulate the assembly of the mitochondrial motor-adaptor complex.
    Kayla Davis, Himanish Basu, Ismael Izquierdo-Villalba, Ethan Shurberg, Thomas L Schwarz.
      Mitochondrial transport relies on a motor-adaptor complex containing Miro1, a mitochondrial outer membrane protein with two GTPase domains, and TRAK1/2, kinesin-1, and dynein. Using a peroxisome-directed Miro1, we quantified the ability of GTPase mutations to influence the peroxisomal recruitment of complex components. Miro1 whose N-GTPase is locked in the GDP state does not recruit TRAK1/2, kinesin, or P135 to peroxisomes, whereas the GTP state does. Similarly, the expression of the MiroGAP VopE dislodges TRAK1 from mitochondria. Miro1 C-GTPase mutations have little influence on complex recruitment. Although Miro2 is thought to support mitochondrial motility, peroxisome-directed Miro2 did not recruit the other complex components regardless of the state of its GTPase domains. Neurons expressing peroxisomal Miro1 with the GTP-state form of the N-GTPase had markedly increased peroxisomal transport to growth cones, whereas the GDP-state caused their retention in the soma. Thus, the N-GTPase domain of Miro1 is critical for regulating Miro1's interaction with the other components of the motor-adaptor complex and thereby for regulating mitochondrial motility.
    DOI:  https://doi.org/10.26508/lsa.202201406
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