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      Human mitochondrial ribosomes can switch structural tRNAs – but when and why?

      review-article
      a , b , c
      RNA Biology
      Taylor & Francis
      Human, mammalian, Mitochondria, ribosomes, rRNA, tRNA

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          ABSTRACT

          High resolution cryoEM of mammalian mitoribosomes revealed the unexpected presence of mitochondrially encoded tRNA as a structural component of mitochondrial large ribosomal subunit (mt-LSU). Our previously published data identified that only mitochondrial (mt-) tRNA Phe and mt-tRNA Val can be incorporated into mammalian mt-LSU and within an organism there is no evidence of tissue specific variation. When mt-tRNA Val is limiting, human mitoribosomes can integrate mt-tRNA Phe instead to generate a translationally competent monosome. Here we discuss the possible reasons for and consequences of the observed plasticity of the structural mt-tRNA integration. We also indicate potential direction for further research that could help our understanding of the mechanistic and evolutionary aspects of this unprecedented system.

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          Most cited references37

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          Maintenance and Expression of Mammalian Mitochondrial DNA.

          Mammalian mitochondrial DNA (mtDNA) encodes 13 proteins that are essential for the function of the oxidative phosphorylation system, which is composed of four respiratory-chain complexes and adenosine triphosphate (ATP) synthase. Remarkably, the maintenance and expression of mtDNA depend on the mitochondrial import of hundreds of nuclear-encoded proteins that control genome maintenance, replication, transcription, RNA maturation, and mitochondrial translation. The importance of this complex regulatory system is underscored by the identification of numerous mutations of nuclear genes that impair mtDNA maintenance and expression at different levels, causing human mitochondrial diseases with pleiotropic clinical manifestations. The basic scientific understanding of the mechanisms controlling mtDNA function has progressed considerably during the past few years, thanks to advances in biochemistry, genetics, and structural biology. The challenges for the future will be to understand how mtDNA maintenance and expression are regulated and to what extent direct intramitochondrial cross talk between different processes, such as transcription and translation, is important.
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            Human mitochondrial tRNAs: biogenesis, function, structural aspects, and diseases.

            Mitochondria are eukaryotic organelles that generate most of the energy in the cell by oxidative phosphorylation (OXPHOS). Each mitochondrion contains multiple copies of a closed circular double-stranded DNA genome (mtDNA). Human (mammalian) mtDNA encodes 13 essential subunits of the inner membrane complex responsible for OXPHOS. These mRNAs are translated by the mitochondrial protein synthesis machinery, which uses the 22 species of mitochondrial tRNAs (mt tRNAs) encoded by mtDNA. The unique structural features of mt tRNAs distinguish them from cytoplasmic tRNAs bearing the canonical cloverleaf structure. The genes encoding mt tRNAs are highly susceptible to point mutations, which are a primary cause of mitochondrial dysfunction and are associated with a wide range of pathologies. A large number of nuclear factors involved in the biogenesis and function of mt tRNAs have been identified and characterized, including processing endonucleases, tRNA-modifying enzymes, and aminoacyl-tRNA synthetases. These nuclear factors are also targets of pathogenic mutations linked to various diseases, indicating the functional importance of mt tRNAs for mitochondrial activity.
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              Ribosome. The structure of the human mitochondrial ribosome.

              The highly divergent ribosomes of human mitochondria (mitoribosomes) synthesize 13 essential proteins of oxidative phosphorylation complexes. We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by means of single-particle electron cryogenic microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three ribosomal RNA molecules. The head domain of the small subunit, particularly the messenger (mRNA) channel, is highly remodeled. Many intersubunit bridges are specific to the mitoribosome, which adopts conformations involving ratcheting or rolling of the small subunit that are distinct from those seen in bacteria or eukaryotes. An intrinsic guanosine triphosphatase mediates a contact between the head and central protuberance. The structure provides a reference for analysis of mutations that cause severe pathologies and for future drug design. Copyright © 2015, American Association for the Advancement of Science.
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                Author and article information

                Journal
                RNA Biol
                RNA Biol
                KRNB
                krnb20
                RNA Biology
                Taylor & Francis
                1547-6286
                1555-8584
                2017
                13 September 2017
                13 September 2017
                : 14
                : 12
                : 1668-1671
                Affiliations
                [a ]The Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University , Newcastle upon Tyne, England, UK
                [b ]Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Retzius väg 8, Stockholm, Sweden
                [c ]MRC Mitochondrial Biology Unit , Wellcome Trust/MRC Building, Hills Road, Cambridge, England, UK
                Author notes
                CONTACT Zofia Chrzanowska-Lightowlers zofia.chrzanowska-lightowlers@ 123456ncl.ac.uk The Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University , Newcastle upon Tyne, NE2 4HH, England UK Michal Minczuk mam@ 123456mrc-mbu.cam.ac.uk , MRC Mitochondrial Biology Unit , Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 0XY, England UK
                Article
                1356551
                10.1080/15476286.2017.1356551
                5731804
                28786741
                0d3e16f5-9772-4874-a66a-b2d579417219
                © 2017 The Author(s). Published with license by Taylor & Francis Group, LLC

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 9 June 2017
                : 10 July 2017
                : 11 July 2017
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 40, Pages: 4
                Categories
                Point of View

                Molecular biology
                human,mammalian,mitochondria,ribosomes,rrna,trna
                Molecular biology
                human, mammalian, mitochondria, ribosomes, rrna, trna

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