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