Mitochondria have specialized ribosomes (mitoribosomes) dedicated to the expression of the genetic information encoded by their genomes. Here, using electron cryomicroscopy, we have determined the structure of the 75-component yeast mitoribosome to an overall resolution of 3.3 Å. The mitoribosomal small subunit has been built de novo and includes 15S rRNA and 34 proteins, including 14 without homologs in the evolutionarily related bacterial ribosome. Yeastspecific rRNA and protein elements, including the acquisition of a putatively active enzyme, give the mitoribosome a distinct architecture compared to the mammalian mitoribosome. At an expanded mRNA channel exit, there is a binding platform for translational activators that regulate translation in yeast but not mammalian mitochondria. The structure provides insights into the evolution and species-specific specialization of mitochondrial translation.Mitochondria are eukaryotic organelles that carry out aerobic respiration. Resulting from their likely ancestry as endosymbionts (1), mitochondria retain a vestigial genome of ~3-100 genes depending on the species. All mitochondrial DNA (mtDNA) encodes at least some of the essential transmembrane subunits of the oxidative phosphorylation complexes. To synthesize these proteins, mitochondria have dedicated ribosomes (mitoribosomes). Nearly all mitoribosomal proteins and all translational factors are encoded by nuclear DNA and imported from the cytoplasm, while mtDNA encodes the mitoribosomal RNA (rRNA) and mitochondria-specific transfer RNAs (mt-tRNAs).Mitochondrial translation displays considerable species-specific specialization, largely dictated by the translational requirements of the mitochondrial genome (2). This specialization manifests in the diverse compositions and structures of mitoribosomes, which are distinct from one another and from all known ribosomes despite sharing an ancestor with modern bacterial ribosomes (2, 3).Our current understanding of this diversity at the atomic level is limited to comparisons of the structure of the large subunit of the Saccharomyces cerevisiae mitoribosome (mt-LSU) (4) with the structures of the complete human (5) and porcine (6) mitoribosomes. These † To whom correspondence should be addressed: ramak@mrc-lmb.cam.ac.uk. * This manuscript has been accepted for publication in Science. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencemag.org/. The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the Copyright Act without the prior, written permission of AAAS. Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts comparisons have revealed that the major evolutionary trajectory for mammalian mitoribosomes is the enlargement of the mitoribosomal proteome together with contraction of the mt-rRNA (2, 3, 7). In contrast, the yeast mitoribosome appears to be on an evolutionary path that has not experienced...
The human mitochondrial ribosome (mitoribosome) and associated proteins regulate the synthesis of 13 essential subunits of the oxidative phosphorylation complexes. We report the discovery of a mitoribosome-associated quality control pathway that responds to interruptions during elongation, and we present structures at 3.1- to 3.3-angstrom resolution of mitoribosomal large subunits trapped during ribosome rescue. Release factor homolog C12orf65 (mtRF-R) and RNA binding protein C6orf203 (MTRES1) eject the nascent chain and peptidyl transfer RNA (tRNA), respectively, from stalled ribosomes. Recruitment of mitoribosome biogenesis factors to these quality control intermediates suggests additional roles for these factors during mitoribosome rescue. We also report related cryo–electron microscopy structures (3.7 to 4.4 angstrom resolution) of elongating mitoribosomes bound to tRNAs, nascent polypeptides, the guanosine triphosphatase elongation factors mtEF-Tu and mtEF-G1, and the Oxa1L translocase.
The results suggest that the antioxidant, EGCG, can reduce ECM production, the fibrotic marker CTGF and inhibit contraction of dermal fibroblasts from SSc patients. Furthermore, EGCG was able to suppress intracellular ROS, ERK1/2 kinase signalling and NF-κB activity. Taken together, EGCG may be a possible candidate for therapeutic treatment aimed at reducing both oxidant stress and the fibrotic effects associated with SSc.
Dysregulation of Ca 2+ signaling following oxidative stress is an important pathophysiological mechanism of many chronic neurodegenerative disorders, including Alzheimer's Disease, agerelated macular degeneration, glaucomatous and diabetic retinopathies. However, the underlying mechanisms of disturbed intracellular Ca 2+ signaling remain largely unknown. We here describe a novel mechanism for increased intracellular Ca 2+ release following oxidative stress in a neuronal cell line. Using an experimental approach that included quantitative polymerase chain reaction, quantitative immunoblotting, microfluorimetry and the optical imaging of intracellular Ca 2+ release, we show that sub-lethal tert-butyl hydroperoxide-mediated oxidative stress result in a selective up-regulation of type-2 inositol-1,4,5,-trisphophate receptors. This oxidative stress mediated change was detected both at the transcriptional and translational level and functionally resulted in increased Ca 2+ release into the nucleoplasm from the membranes of the nuclear envelope at a given receptor-specific stimulus. Our data describe a novel source of Ca 2+ dysregulation induced by oxidative stress with potential relevance for differential subcellular Ca 2+ signaling specifically within the nucleus and the development of novel neuroprotective strategies in neurodegenerative disorders.
Ribosome assembly is an essential and conserved process that is regulated at each step by specific factors. Using cryo-electron microscopy (cryo-EM), we visualize the formation of the conserved peptidyl transferase center (PTC) of the human mitochondrial ribosome. The conserved GTPase GTPBP7 regulates the correct folding of 16S ribosomal RNA (rRNA) helices and ensures 2ʹ-O-methylation of the PTC base U3039. GTPBP7 binds the RNA methyltransferase NSUN4 and MTERF4, which sequester H68-71 of the 16S rRNA and allow biogenesis factors to access the maturing PTC. Mutations that disrupt binding of their Caenorhabditis elegans orthologs to the large subunit potently activate mitochondrial stress and cause viability, development, and sterility defects. Next-generation RNA sequencing reveals widespread gene expression changes in these mutant animals that are indicative of mitochondrial stress response activation. We also answer the long-standing question of why NSUN4, but not its enzymatic activity, is indispensable for mitochondrial protein synthesis.
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