title: Overexpression of the mitochondrial methyltransferase TFB1M in the mouse does not impact mitoribosomal methylation status or hearing.
abstract: Mitochondrial dysfunction is a well-established cause of sensorineural deafness, but the pathophysiological events are poorly understood. Non-syndromic deafness and predisposition to aminoglycoside-induced deafness can be caused by specific mutations in the 12S rRNA gene of mtDNA and are thus maternally inherited traits. The pathophysiology induced by mtDNA mutations has traditionally been attributed to deficient oxidative phosphorylation, which causes energy crisis with functional impairment of multiple cellular processes. In contrast, it was recently reported that signaling induced by 'hypermethylation' of two conserved adenosines of 12S rRNA in the mitoribosome is of key pathophysiological importance in sensorineural deafness. In support for this concept, it was reported that overexpression of the essential mitochondrial methyltransferase TFB1M in the mouse was sufficient to induce mitoribosomal hypermethylation and deafness. At variance with this model, we show here that 12S rRNA is near fully methylated in vivo in the mouse and thus cannot be further methylated to any significant extent. Furthermore, bacterial artificial chromosome transgenic mice overexpressing TFB1M have no increase of 12S rRNA methylation levels and hear normally. We thus conclude that therapies directed against mitoribosomal methylation are unlikely to be beneficial to patients with sensorineural hearing loss or other types of mitochondrial disease.
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden.
authors.forename: Seungmin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Rose
authors.affiliation: INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
authors.forename: Metodi D
authors.initials: MD
authors.lastname: Metodiev
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Munich/Neuherberg, Germany, Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Munich/Neuherberg, Germany, Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany, German Center for Vertigo and Balance Disorders, Munich, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Vernaleken
authors.affiliation: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany, German Center for Vertigo and Balance Disorders, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Munich/Neuherberg, Germany.
authors.forename: Valerie
authors.initials: V
authors.lastname: Gailus-Durner
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Munich/Neuherberg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Munich/Neuherberg, Germany, German Center for Vertigo and Balance Disorders, Munich, Germany, Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85354 Freising-Weihenstephan, Germany, German Center for Diabetes Research (DZD), Ingostaedter Landstr. 1, 85764 Neuherberg, Germany and.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě De Angelis
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark.
authors.forename: Stephen
authors.initials: S
authors.lastname: Douthwaite
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden, Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany larsson@age.mpg.de.
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
mesh_terms: D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics*; D003638:Deafness / Q000235:genetics; D005260:Female; D006309:Hearing / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced / Q000235:genetics; D008297:Male; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D000069396:Mitochondrial Ribosomes / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics; D012335:RNA, Ribosomal / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S; C462441:Tfb1m protein, mouse; D014157:Transcription Factors