MTO1 mediates tissue specificity of OXPHOS defects via tRNA modification and translation optimization, which can be bypassed by dietary intervention
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Mitochondrial Diseases
genetics [Mitochondrial Diseases] Mitochondrial translation Mitochondrion genetics [Carrier Proteins] Mto1 protein mouse Oxidative Phosphorylation Mice 0302 clinical medicine RNA Transfer Protein biosynthesis metabolism [RNA Transfer] Genetics (clinical) Genetics 0303 health sciences Proteolytic enzymes RNA-Binding Proteins Translation (biology) General Medicine Articles chemistry [Carrier Proteins] ddc Cell biology Mitochondria Organ Specificity metabolism [Mitochondrial Diseases] Transfer RNA genetics [RNA Transfer] Diet Ketogenic metabolism [Fibroblasts] TRNA modification Diet therapy drug therapy [Mitochondrial Diseases] Molecular Sequence Data Biology Mitochondrial Proteins 03 medical and health sciences ddc:570 Animals Humans Amino Acid Sequence Molecular Biology 030304 developmental biology Fibroblasts metabolism [Mitochondria] MTO1 protein human Protein Biosynthesis Carrier Proteins Sequence Alignment 030217 neurology & neurosurgery metabolism [Carrier Proteins] |
| Zdroj: | Human molecular genetics 24(8), 2247-2266 (2014). doi:10.1093/hmg/ddu743 Hum. Mol. Genet. 24, 2247-2266 (2015) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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