Mitochondrial RNA modifications shape metabolic plasticity in metastasis

• Published in: Nature (London) 2022-07, Vol.607 (7919), p.593-603
• Main Authors: Delaunay, Sylvain, Pascual, Gloria, Feng, Bohai, Klann, Kevin, Behm, Mikaela, Hotz-Wagenblatt, Agnes, Richter, Karsten, Zaoui, Karim, Herpel, Esther, Münch, Christian, Dietmann, Sabine, Hess, Jochen, Benitah, Salvador Aznar, Frye, Michaela
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 14/1; 14/19; 14/28; 14/5; 14/63; 38/39; 38/77; 38/79; 45/91; 631/67/1536/1665; 631/80/304; Cancer; CD36 antigen; Cell viability; Glycolysis; Head & neck cancer; Humanities and Social Sciences; Metabolism; Metabolites; Metastases; Metastasis; Mitochondria; Mitochondrial DNA; mRNA; multidisciplinary; Oral cancer; Oxidative phosphorylation; Phosphorylation; Plastic properties; Plasticity; Protein synthesis; Proteins; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Therapeutic targets; Transfer RNA; Translation; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-04898-5

Aggressive and metastatic cancers show enhanced metabolic plasticity 1 , 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 (m 5 C) and its derivative 5-formylcytosine (f 5 C) (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 m 5 C at position 34 in mitochondrial tRNA Met . m 5 C-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 m 5 C-deficient tumours do not metastasize efficiently. We discovered that CD36-dependent non-dividing, metastasis-initiating tumour cells require mitochondrial m 5 C 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.