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Schöller, E.* ; Marks, J.* ; Marchand, V.* ; Bruckmann, A.* ; Powell, C.A.* ; Reichold, M.* ; Mutti, C.D.* ; Dettmer, K.* ; Feederle, R. ; Hüttelmaier, S.* ; Helm, M.* ; Oefner, P.* ; Minczuk, M.* ; Motorin, Y.* ; Hafner, M.* ; Meister, G.*

Balancing of mitochondrial translation through METTL8-mediated m3C modification of mitochondrial tRNAs.

Mol. Cell 81, 4810-4825.e12 (2021)
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Mitochondria contain a specific translation machinery for the synthesis of mitochondria-encoded respiratory chain components. Mitochondrial tRNAs (mt-tRNAs) are also generated from the mitochondrial DNA and, similar to their cytoplasmic counterparts, are post-transcriptionally modified. Here, we find that the RNA methyltransferase METTL8 is a mitochondrial protein that facilitates 3-methyl-cytidine (m3C) methylation at position C32 of the mt-tRNASer(UCN) and mt-tRNAThr. METTL8 knockout cells show a reduction in respiratory chain activity, whereas overexpression increases activity. In pancreatic cancer, METTL8 levels are high, which correlates with lower patient survival and an enhanced respiratory chain activity. Mitochondrial ribosome profiling uncovered mitoribosome stalling on mt-tRNASer(UCN)- and mt-tRNAThr-dependent codons. Further analysis of the respiratory chain complexes using mass spectrometry revealed reduced incorporation of the mitochondrially encoded proteins ND6 and ND1 into complex I. The well-balanced translation of mt-tRNASer(UCN)- and mt-tRNAThr-dependent codons through METTL8-mediated m3C32 methylation might, therefore, facilitate the optimal composition and function of the mitochondrial respiratory chain.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Mettl8 ; Rna Modification ; M(3)c ; Mt-trna ; Translation; Messenger-rna; Posttranscriptional Modifications; M(6)a Methyltransferase; Sequence; Transcription; Methylation; Complex; Mettl16; Fate
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 1097-2765
e-ISSN 1097-4164
Journal Molecular Cell
Quellenangaben Volume: 81, Issue: 23, Pages: 4810-4825.e12 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) CF Monoclonal Antibodies (CF-MAB)
POF-Topic(s) 30201 - Metabolic Health
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-502210-001
Grants Medical Research Council
European Research Council (ERC)
Grand Est Region (France) FRCR grant EpiARN
Bavarian Systems-Biology Network (Bio-SysNet)
Deutsche Forschungsgemeinschaft (DFG)
DOI 10.1016/j.molcel.2021.10.018
WOS ID WOS:000728513200008
Scopus ID 85119899368
PubMed ID 34774131
Erfassungsdatum 2021-12-10
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