Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3

Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039.

Lindsey Van Haute ¹, Sabine Dietmann ², Laura Kremer ³ ⁴, Shobbir Hussain ⁵, Sarah F Pearce ¹, Christopher A Powell ¹, Joanna Rorbach ¹, Rebecca Lantaff ⁶, Sandra Blanco ², Sascha Sauer ⁷ ⁸ ⁹, Urania Kotzaeridou ¹⁰, Georg F Hoffmann ¹⁰, Yasin Memari ¹¹, Anja Kolb-Kokocinski ¹¹, Richard Durbin ¹¹, Johannes A Mayr ¹², Michaela Frye ², Holger Prokisch ³ ⁴, Michal Minczuk ¹

Affiliations

1 MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
2 Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
3 Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Institute of Human Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
4 Technical University Munich, Institute of Human Genetics, Trogerstrasse 32, 81675 München, Germany.
5 Department of Biology &Biochemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
6 Department of Physiology Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK.
7 Max-Planck-Institute for Molecular Genetics, Otto-Warburg Laboratory, 14195 Berlin, Germany.
8 University of Würzburg, CU Systems Medicine, 97080 Würzburg, Germany.
9 Max-Delbrück-Center for Molecular Medicine, Berlin Institute for Medical Systems Biology/Berlin Institute of Health, 13125 Berlin, Germany.
10 Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital, 69120 Heidelberg, Germany.
11 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
12 Department of Paediatrics, Paracelsus Medical University, SALK Salzburg, Salzburg 5020, Austria.

PMID: 27356879 DOI: 10.1038/ncomms12039

Abstract

Epitranscriptome modifications are required for structure and function of RNA and defects in these pathways have been associated with human disease. Here we identify the RNA target for the previously uncharacterized 5-methylcytosine (m(5)C) methyltransferase NSun3 and link m(5)C RNA modifications with energy metabolism. Using whole-exome Sequencing, we identified loss-of-function mutations in NSUN3 in a patient presenting with combined mitochondrial respiratory chain complex deficiency. Patient-derived fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of NSun3. We show that NSun3 is required for deposition of m(5)C at the anticodon loop in the mitochondrially encoded transfer RNA methionine (mt-tRNA(Met)). Further, we demonstrate that m(5)C deficiency in mt-tRNA(Met) results in the lack of 5-formylcytosine (f(5)C) at the same tRNA position. Our findings demonstrate that NSUN3 is necessary for efficient mitochondrial translation and reveal that f(5)C in human mitochondrial RNA is generated by oxidative processing of m(5)C.

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