Mitochondrial RNA modifications shape metabolic plasticity in metastasis

Abstract

Aggressive and metastatic cancers show enhanced metabolic plasticity1, but the precise underlying mechanisms of this remain unclear. Here we show how two NOP2/Sun RNA methyltransferase 3 (NSUN3)-dependent RNA modifications—5-methylcytosine (m5C) and its derivative 5-formylcytosine (f5C) (refs.2–4)—drive the translation of mitochondrial mRNA to power metastasis. Translation of mitochondrially encoded subunits of the oxidative phosphorylation complex depends on the formation of m5C at position 34 in mitochondrial tRNAMet. m5C-deficient human oral cancer cells exhibit increased levels of glycolysis and changes in their mitochondrial function that do not affect cell viability or primary tumour growth in vivo; however, metabolic plasticity is severely impaired as mitochondrial m5C-deficient tumours do not metastasize efficiently. 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 patients with head and neck cancer is predictive for metastasis and disease progression. Finally, we confirm that this metabolic switch that allows the metastasis of tumour cells can be pharmacologically targeted through the inhibition of mitochondrial mRNA translation in vivo. Together, our results reveal that site-specific mitochondrial RNA modifications could be therapeutic targets to combat metastasis.

An Epigenetic Role of Mitochondria in Cancer

“…Mitochondria possess specific translation machinery for the synthesis of proteins in ETC, and tRNA modification is indispensable during mitochondrial translation and the OXPHOS process, which require folate-dependent tRNA methylation [ 140 ]. A recent study indicates that mitochondrial tRNA methylation is necessary for tumor metastasis due to its critical role in mitochondria gene translation [ 141 ]. Moreover, tRNA methyltransferase 10C (TRMT10C), catalyzing the mitochondrial ND5 mRNA at N1-methyladenosine (m 1 A) site, promotes cancer cell metabolism by reducing the mitochondrial ribonuclease P protein 1 (MRPP1) in mitochondria and inducing protein instability and mt-tRNA processing [ 142 ].…”

Lipid but not glucose metabolism is associated with 18FDG-PET/CT false negative lymph nodes in head and neck cancer

“…Regarding CD36, a series of studies have demonstrated its metastasis-promoting functions [26][27][28][29]. However, CD36 has not been applied with 18 FDG-PET/CT for distinguishing false negatives.…”

Human NOP2/NSUN1 Regulates Ribosome Biogenesis Through Non-Catalytic Complex Formation with Box C/D snoRNPs

“…The biological impact and extent of RNA cytosine methylation are not entirely understood. However, the functional characterizations of NSUN proteins and the identification of their RNA substrates have helped uncover several essential roles played in the regulation of nuclear and mitochondrial gene expression (14,(18)(19)(20). Mutations and changes in expression levels of genes coding for several NSUN proteins have been linked with diverse human diseases ranging from neurological disorders (21) to cancer (22)(23)(24), highlighting the importance of further characterizing this family of RNA methyltransferases.…”