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Tischner, C.* ; Hofer, A.* ; Wulff, V.* ; Stepek, J.* ; Dumitru, I.* ; Becker, L. ; Haack, T.B. ; Kremer, L.S. ; Datta, A.N.* ; Sperl, W.* ; Floß, T. ; Wurst, W. ; Chrzanowska-Lightowlers, Z.M.* ; Hrabě de Angelis, M. ; Klopstock, T. ; Prokisch, H. ; Wenz, T.*

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)
Verlagsversion DOI PMC
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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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
Sprache englisch
Veröffentlichungsjahr 2015
HGF-Berichtsjahr 2015
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
Verlagsort Oxford
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Experimental Genetics (IEG)
Institute of Human Genetics (IHG)
Institute of Developmental Genetics (IDG)
POF Topic(s) 30201 - Metabolic Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30204 - Cell Programming and Repair
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500600-003
G-500600-001
G-500700-001
G-500500-001
PubMed ID 25552653
DOI 10.1093/hmg/ddu743
WOS ID WOS:000353066200012
Scopus ID 84926472434
Erfassungsdatum 2015-01-05
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