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3-methylcytosine: a novel mitochondrial mRNA modification: From physiology to pathology

par Penning, Audrey
Président du jury Langer, Ingrid
Promoteur Fuks, François
Publication Non publié, 2023-04-21

Thèse de doctorat

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Résumé :

A novel pillar of epigenetics has recently gained the attention of the scientific community: mRNA modifications. This new field, commonly referred to as “epitranscriptomics”, has emerged as a crucial regulatory level of gene expression. Yet, the study of these modifications is still in its early days and has definitely not reached its full potential.The presence of modifications in mitochondrial mRNAs has emerged very recently, and is suggested to play a role in fine-tuning mitochondrial gene expression and function. However, the epitranscriptomic landscape of mitochondrial mRNA remains very poorly explored. The aim of this thesis was to investigate a novel mitochondrial mRNA modification: the N3- methylcytosine (m3C), from its physiological to its pathological relevance.In the first part of this thesis, we show that METTL8 catalyzes m3C on mitochondrial mRNA, specifically on complex I subunits transcripts of the electron transport chain (ETC). Furthermore, we report that METTL8 influences the protein level of its modified targets, and therefore regulates the complex I activity. Finally, we confirm the complex I deficiency in a Mettl8-knockout mouse model, that we established.In the second part of this thesis, we aimed to tackle the pathological impact of this modification. In regard to the emerging crosstalk between cervical cancer and mitochondria, we decided to investigate for the first time, the potential pathological role of m3C in cervical cancer. First, we confirmed that METTL8 expression is higher in patient’s biopsies compared to normal cervical tissues, and correlates with the disease progression. We then showed that METTL8-dependent m3C promotes cell proliferation and migration; and tumor growth in a xenografts model. Furthermore, we decipher that METTL8-driven signature is enriched for mitochondrial functions and complex I activity.In conclusion, our findings improve our understanding of this emerging epitranscriptomic field, and specifically unravel the landscape of mitochondrial mRNA modifications, from physiological to pathological perspectives. Overall, our results could contribute to a better knowledge of the role of epitranscriptomics in health and disease.