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MTO1 mediates tissue-specificity of OXPHOS defects via tRNA modification and translation optimization, which can be bypassed by dietary intervention.
Hum. Mol. Genet. 24, 2247-2266 (2015)
DOI PMC
Verlagsversion online verfügbar vsl. 01/2016 
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 KO 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Wobble Modification Deficiency; Respiratory-chain Deficiency; Human Mitochondrial Diseases; Mutant Transfer-rnas; Oxidative-phosphorylation; Lactic-acidosis; In-vivo; Hypertrophic Cardiomyopathy; Protein-synthesis; Escherichia-coli
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Zeitschrift Human Molecular Genetics
Quellenangaben Band: 24, Heft: 8, Seiten: 2247-2266 Artikelnummer: , Supplement: ,
Verlag Oxford University Press ; HighWire Press
Verlagsort Oxford
Begutachtungsstatus peer-reviewed