title: MTO1 mediates tissue specificity of OXPHOS defects via tRNA modification and translation optimization, which can be bypassed by dietary intervention.
abstract: Mitochondrial diseases often exhibit tissue-specific pathologies, but this phenomenon is poorly understood. Here we present regulation of mitochondrial translation by the Mitochondrial Translation Optimization Factor 1, MTO1, as a novel player in this scenario. We demonstrate that MTO1 mediates tRNA modification and controls mitochondrial translation rate in a highly tissue-specific manner associated with tissue-specific OXPHOS defects. Activation of mitochondrial proteases, aberrant translation products, as well as defects in OXPHOS complex assembly observed in MTO1 deficient mice further imply that MTO1 impacts translation fidelity. In our mouse model, MTO1-related OXPHOS deficiency can be bypassed by feeding a ketogenic diet. This therapeutic intervention is independent of the MTO1-mediated tRNA modification and involves balancing of mitochondrial and cellular secondary stress responses. Our results thereby establish mammalian MTO1 as a novel factor in the tissue-specific regulation of OXPHOS and fine tuning of mitochondrial translation accuracy.
authors.affiliation: Institute for Genetics and Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47A, Cologne 50674, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Tischner
authors.affiliation: Institute for Genetics and Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47A, Cologne 50674, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Hofer
authors.affiliation: Institute for Genetics and Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47A, Cologne 50674, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Wulff
authors.affiliation: Institute for Genetics and Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47A, Cologne 50674, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Stepek
authors.affiliation: Institute for Genetics and Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47A, Cologne 50674, Germany.
authors.forename: Iulia
authors.initials: I
authors.lastname: Dumitru
authors.affiliation: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich 80336, Germany, German Mouse Clinic, Institute of Experimental Genetics.
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.affiliation: Institute of Human Genetics, German Network for Mitochondrial Disorders (mitoNET), Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Haack
authors.affiliation: Institute of Human Genetics, German Network for Mitochondrial Disorders (mitoNET), Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Kremer
authors.affiliation: Division of Neuropediatrics and Developmental Medicine, University Children's Hospital Basel (UKBB), University of Basel, Basel 4031, Switzerland.
authors.forename: Alexandre N
authors.initials: AN
authors.lastname: Datta
authors.affiliation: German Network for Mitochondrial Disorders (mitoNET), Germany, Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health (GmbH), Neuherberg 85764, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Floss
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health (GmbH), Neuherberg 85764, Germany, Technical University Munich, Helmholtz Zentrum München, Neuherberg 85764, Germany, DZNE-German Center for Neurodegenerative Diseases, Munich, Germany, Max Planck Institute of Psychiatry, Munich 80804, Germany, German Center for Vertigo and Balance Disorders, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.affiliation: The Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, The Medical School, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Zofia
authors.initials: Z
authors.lastname: Chrzanowska-Lightowlers
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, German Center for Vertigo and Balance Disorders, Munich, Germany, Center of Life and Food Sciences Weihenstephan, Technische Universitat München, Freising 85350, Germany, German Center for Diabetes Research (DZD), Neuherberg 85764, Germany and Technische Universität München, Freising-Weihenstephan 85354, Germany.
authors.forename: Martin Hrabe
authors.initials: MH
authors.lastname: De Angelis
authors.affiliation: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich 80336, Germany, German Mouse Clinic, Institute of Experimental Genetics, German Network for Mitochondrial Disorders (mitoNET), Germany, DZNE-German Center for Neurodegenerative Diseases, Munich, Germany, German Center for Vertigo and Balance Disorders, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.affiliation: Institute of Human Genetics, Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health (GmbH), Neuherberg 85764, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Institute for Genetics and Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47A, Cologne 50674, Germany, German Network for Mitochondrial Disorders (mitoNET), Germany, tina.wenz@uni-koeln.de.
authors.forename: Tina
authors.initials: T
authors.lastname: Wenz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055423:Diet, Ketogenic; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010085:Oxidative Phosphorylation; D014176:Protein Biosynthesis; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D016415:Sequence Alignment
chemical_list: D002352:Carrier Proteins; C492006:MTO1 protein, human; D024101:Mitochondrial Proteins; C492007:Mto1 protein, mouse; D016601:RNA-Binding Proteins; D012343:RNA, Transfer