1. Academic Validation
  2. Balancing of mitochondrial translation through METTL8-mediated m3C modification of mitochondrial tRNAs

Balancing of mitochondrial translation through METTL8-mediated m3C modification of mitochondrial tRNAs

  • Mol Cell. 2021 Dec 2;81(23):4810-4825.e12. doi: 10.1016/j.molcel.2021.10.018.
Eva Schöller 1 James Marks 2 Virginie Marchand 3 Astrid Bruckmann 1 Christopher A Powell 4 Markus Reichold 5 Christian Daniel Mutti 4 Katja Dettmer 6 Regina Feederle 7 Stefan Hüttelmaier 8 Mark Helm 9 Peter Oefner 6 Michal Minczuk 4 Yuri Motorin 10 Markus Hafner 2 Gunter Meister 11
Affiliations

Affiliations

  • 1 Regensburg Center for Biochemistry (RCB), Laboratory for RNA Biology, University of Regensburg, 93053 Regensburg, Germany.
  • 2 RNA Molecular Biology Group, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  • 3 Université de Lorraine, CNRS, INSERM, UMS2008/US40 IBSLor, EpiRNA-Seq Core facility, 54000 Nancy, France.
  • 4 Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK.
  • 5 Medical Cell Biology, Institute of Physiology, University of Regensburg, 93053 Regensburg, Germany.
  • 6 Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
  • 7 Monoclonal Antibody Core Facility, Institute for Diabetes and Obesity, Helmholtz-Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
  • 8 Institute of Molecular Medicine, Section for Molecular Cell Biology, Faculty of Medicine, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany.
  • 9 Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Staudingerweg 5, 55128 Mainz, Germany.
  • 10 Université de Lorraine, CNRS, INSERM, UMS2008/US40 IBSLor, EpiRNA-Seq Core facility, 54000 Nancy, France; Université de Lorraine, CNRS, UMR7365 IMoPA, 54000 Nancy, France.
  • 11 Regensburg Center for Biochemistry (RCB), Laboratory for RNA Biology, University of Regensburg, 93053 Regensburg, Germany. Electronic address: gunter.meister@ur.de.
Abstract

Mitochondria contain a specific translation machinery for the synthesis of mitochondria-encoded respiratory chain components. Mitochondrial tRNAs (mt-tRNAs) are also generated from the mitochondrial DNA and, similar to their cytoplasmic counterparts, are post-transcriptionally modified. Here, we find that the RNA methyltransferase METTL8 is a mitochondrial protein that facilitates 3-methyl-cytidine (m3C) methylation at position C32 of the mt-tRNASer(UCN) and mt-tRNAThr. METTL8 knockout cells show a reduction in respiratory chain activity, whereas overexpression increases activity. In pancreatic Cancer, METTL8 levels are high, which correlates with lower patient survival and an enhanced respiratory chain activity. Mitochondrial ribosome profiling uncovered mitoribosome stalling on mt-tRNASer(UCN)- and mt-tRNAThr-dependent codons. Further analysis of the respiratory chain complexes using mass spectrometry revealed reduced incorporation of the mitochondrially encoded proteins ND6 and ND1 into complex I. The well-balanced translation of mt-tRNASer(UCN)- and mt-tRNAThr-dependent codons through METTL8-mediated m3C32 methylation might, therefore, facilitate the optimal composition and function of the mitochondrial respiratory chain.

Keywords

METTL8; RNA modification; m(3)C; mt-tRNA; translation.

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