m3C is a mitochondrial mRNA modification which promotes tumor progression

Penning, A.; Wang, K.; Celerier, M.; Collignon, E.; Primac, I.; Van der Linden, L.; Bizet, M.; Calonne, E.; Hassabi, B.; Hubert, C.; Putmans, P.; Murisier, F.; Larbanoix, L.; Achouri, Y.; Lan, J.; Nemazanyy, I.; Laurent, S.; Jacquemin, P.; Yi, C.; Deplus, R.; Fuks, F.

doi:10.1101/2025.01.15.633161

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bioRxiv · 10.1101/2025.01.15.633161

m3C is a mitochondrial mRNA modification which promotes tumor progression

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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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Penning, A., Wang, K., Celerier, M., Collignon, E., Primac, I., Van der Linden, L., Bizet, M., Calonne, E., Hassabi, B., Hubert, C., Putmans, P., Murisier, F., Larbanoix, L., Achouri, Y., Lan, J., Nemazanyy, I., Laurent, S., Jacquemin, P., Yi, C., Deplus, R., Fuks, F.. 2025-01-16. m3C is a mitochondrial mRNA modification which promotes tumor progression. https://doi.org/10.1101/2025.01.15.633161

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