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

Authors :
Thomas Klopstock
Veronika Wulff
Alexandre N. Datta
Thomas Floss
Christin Tischner
Martin Hrabé de Angelis
Wolfgang Sperl
Zofia M.A. Chrzanowska-Lightowlers
Wolfgang Wurst
Holger Prokisch
Tobias B. Haack
Lore Becker
Annette Hofer
Iulia Dumitru
Laura S. Kremer
Joanna Magdalena Stepek
Tina Wenz
Source :
Human molecular genetics 24(8), 2247-2266 (2014). doi:10.1093/hmg/ddu743, Hum. Mol. Genet. 24, 2247-2266 (2015)
Publication Year :
2015
Publisher :
Oxford Univ. Press, 2015.

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.

Details

Language :
English
Database :
OpenAIRE
Journal :
Human molecular genetics 24(8), 2247-2266 (2014). doi:10.1093/hmg/ddu743, Hum. Mol. Genet. 24, 2247-2266 (2015)
Accession number :
edsair.doi.dedup.....fab91d4b56b275106bac2efd5065e987
Full Text :
https://doi.org/10.1093/hmg/ddu743