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

Christin Tischner, Annette Hofer, Veronika Wulff, Joanna Stepek, Iulia Dumitru, Lore Becker, Tobias Haack, Laura Kremer, Alexandre N. Datta, Wolfgang Sperl, Thomas Floss, W. Wolfgang Wurst, Zofia Chrzanowska-Lightowlers, Martin Hrabe De Angelis, Thomas Klopstock, Holger Prokisch, Tina Wenz

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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, aswell as defects in OXPHOS complex assembly observed in MTO1 deficient mice further imply thatMTO1 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.

Original languageEnglish
Pages (from-to)2247-2266
Number of pages20
JournalHuman Molecular Genetics
Volume24
Issue number8
DOIs
StatePublished - 15 Apr 2015

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