Mitochondrial RNA modifications shape metabolic plasticity in metastasis

Nature. 2022 Jul;607(7919):593-603. doi: 10.1038/s41586-022-04898-5. Epub 2022 Jun 29.


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.

MeSH terms

  • 5-Methylcytosine* / biosynthesis
  • 5-Methylcytosine* / metabolism
  • CD36 Antigens
  • Cell Survival
  • Cytosine / analogs & derivatives*
  • Cytosine / metabolism
  • Disease Progression
  • Glycolysis* / drug effects
  • Humans
  • Methylation / drug effects
  • Methyltransferases / antagonists & inhibitors
  • Methyltransferases / metabolism
  • Mitochondria* / drug effects
  • Mitochondria* / genetics
  • Mitochondria* / metabolism
  • Mouth Neoplasms / genetics
  • Mouth Neoplasms / metabolism
  • Mouth Neoplasms / pathology
  • Neoplasm Metastasis* / drug therapy
  • Neoplasm Metastasis* / genetics
  • Neoplasm Metastasis* / pathology
  • Oxidative Phosphorylation* / drug effects
  • Protein Biosynthesis / drug effects
  • RNA, Mitochondrial* / genetics
  • RNA, Mitochondrial* / metabolism
  • RNA, Transfer, Met / genetics
  • RNA, Transfer, Met / metabolism


  • 5-formylcytosine
  • CD36 Antigens
  • RNA, Mitochondrial
  • RNA, Transfer, Met
  • 5-Methylcytosine
  • Cytosine
  • Methyltransferases
  • NSUN3 protein, human