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MTO1 mediates tissue specificity of OXPHOS defects via tRNA modification and translation optimization, which can be bypassed by dietary intervention.

  • Tischner C Institute for Genetics and Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47A, Cologne 50674, Germany.
  • Hofer A Institute for Genetics and Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47A, Cologne 50674, Germany.
  • Wulff V Institute for Genetics and Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47A, Cologne 50674, Germany.
  • Stepek J Institute for Genetics and Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47A, Cologne 50674, Germany.
  • Dumitru I Institute for Genetics and Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47A, Cologne 50674, Germany.
  • Becker L Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich 80336, Germany, German Mouse Clinic, Institute of Experimental Genetics.
  • Haack T Institute of Human Genetics, German Network for Mitochondrial Disorders (mitoNET), Germany.
  • Kremer L Institute of Human Genetics, German Network for Mitochondrial Disorders (mitoNET), Germany.
  • Datta AN Division of Neuropediatrics and Developmental Medicine, University Children's Hospital Basel (UKBB), University of Basel, Basel 4031, Switzerland.
  • Sperl W German Network for Mitochondrial Disorders (mitoNET), Germany, Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
  • Floss T Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health (GmbH), Neuherberg 85764, Germany.
  • Wurst W 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.
  • Chrzanowska-Lightowlers Z The Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, The Medical School, Newcastle upon Tyne NE2 4HH, UK.
  • De Angelis MH 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.
  • Klopstock T 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.
  • Prokisch H Institute of Human Genetics, Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health (GmbH), Neuherberg 85764, Germany.
  • Wenz T 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.
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  • 2015-01-02
Published in:
  • Human molecular genetics. - 2015
Amino Acid Sequence
Animals
Carrier Proteins
Diet, Ketogenic
Fibroblasts
Humans
Mice
Mitochondria
Mitochondrial Diseases
Mitochondrial Proteins
Molecular Sequence Data
Organ Specificity
Oxidative Phosphorylation
Protein Biosynthesis
RNA, Transfer
Sequence Alignment
English 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.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/53481
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