Mitochondrial RNA modifications shape metabolic plasticity in metastasis

Aggressive and metastatic cancers show enhanced metabolic plasticity, but the precise underlying mechanisms for this remain unclear. Here, we reveal how two NSUN3-dependent RNA modifications, 5-methylcytosine (m⁵C) and its derivative 5-formylcytosine (f⁵C), drive mitochondrial mRNA translation to power metastasis. Translation of mitochondrial-encoded subunits of the oxidative phosphorylation (OXPHOS) complex depends on the formation of m⁵C at position 34 in mitochondrial tRNA^Met. m⁵C-deficient human oral cancer cells enhance glycolysis and adapt mitochondrial function without affecting cell viability or primary tumour growth in vivo; however, metabolic plasticity is severely impaired as mitochondrial m⁵C-deficient tumours fail to efficiently metastasize. We discovered that CD36-dependent non-dividing, metastasis-initiating tumour cells require mitochondrial m⁵C to activate invasion and dissemination. Moreover, a mitochondria-driven gene signature in head and neck cancer patients is predictive for metastasis and disease progression. Finally, we confirm that this metabolic switch allowing tumour cell metastasis can be pharmacologically targeted through inhibition of mitochondrial mRNA translation in vivo. Together, our results reveal site-specific mitochondrial RNA modifications as novel therapeutic targets to fight metastasis.

This Script was made to analyze the RNAseq data from VDH15 cell line infected with shRNA control (Ctr) or targeting NSUN3 (sh#1, sh#2), injected in mice, tumors collected 21days after infection, and cancer cell lines sorted.