m3C is a mitochondrial mRNA modification which promotes tumor progression

Audrey Penning; Kun Wang; Margot Celerier; Évelyne Collignon; Irina Primac; Louis Van der Linden; Martin Bizet; Emilie Calonne; Bouchra Hassabi; Céline Hubert; Pascale Putmans; Frédéric Murisier; Lionel Larbanoix; Younès Achouri; Jie Lan; Ivan Nemazanyy; Sophie Laurent; Patrick Jacquemin; Chengqi Yi; Rachel Deplus; François Fuks

doi:10.1101/2025.01.15.633161

Cell BiologybioRxivJan 15, 2025

Preprint

m3C is a mitochondrial mRNA modification which promotes tumor progression

Audrey Penning iD, Kun Wang iD, Margot Celerier, Évelyne Collignon iD, Irina Primac iD, Louis Van der Linden, Martin Bizet iD, Emilie Calonne iD, Bouchra Hassabi, Céline Hubert, Pascale Putmans, Frédéric Murisier, Lionel Larbanoix iD, Younès Achouri iD, Jie Lan, Ivan Nemazanyy iD, Sophie Laurent iD, Patrick Jacquemin iD, Chengqi Yi iD, Rachel Deplus, François Fuks iD

Abstract

Mitochondrial mRNA modifications are suggested to play a role in fine-tuning mitochondrial gene expression and function. However, the epitranscriptomic landscape of mitochondrial mRNA (mt-mRNA) remains poorly explored. Here, we uncover N3-methylcytosine (m3C) as a novel mt-mRNA that is catalyzed by METTL8, an enzyme previously known to modify mt-tRNA. Transcriptome-wide mapping reveals that METTL8-dependent m3C is enriched in mt-mRNAs encoding complex I subunits of the respiratory chain. Additionally, METTL8 is highly expressed in various cancers, notably in cervical cancer. METTL8 depletion impairs cell migration in vitro and reduces tumor growth in mouse xenografts. Finally, transcriptomic analyses further link METTL8 expression to oncogenic pathways, mitochondrial functions and complex I activity. Together, our results reveal a novel mitochondrial mRNA modification that promotes cancer progression.

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