Balancing of mitochondrial translation through METTL8-mediated mC modification of mitochondrial tRNAs.
Fiche publication
Date publication
novembre 2021
Journal
Molecular cell
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MOTORINE Iouri, Dr MARCHAND Virginie
Tous les auteurs :
Schöller E, Marks J, Marchand V, Bruckmann A, Powell CA, Reichold M, Mutti CD, Dettmer K, Feederle R, Hüttelmaier S, Helm M, Oefner P, Minczuk M, Motorin Y, Hafner M, Meister G
Lien Pubmed
Résumé
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 (mC) methylation at position C of the mt-tRNA and mt-tRNA. 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-tRNA- and mt-tRNA-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-tRNA- and mt-tRNA-dependent codons through METTL8-mediated mC methylation might, therefore, facilitate the optimal composition and function of the mitochondrial respiratory chain.
Mots clés
METTL8, RNA modification, m(3)C, mt-tRNA, translation
Référence
Mol Cell. 2021 Nov 8;: