TY - JOUR
T1 - Mitochondrial RNA modifications shape metabolic plasticity in metastasis
AU - Delaunay, Sylvain
AU - Pascual, Gloria
AU - Feng, Bohai
AU - Klann, Kevin
AU - Behm, Mikaela
AU - Hotz-Wagenblatt, Agnes
AU - Richter, Karsten
AU - Zaoui, Karim
AU - Herpel, Esther
AU - Münch, Christian
AU - Dietmann, Sabine
AU - Hess, Jochen
AU - Benitah, Salvador Aznar
AU - Frye, Michaela
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/7/21
Y1 - 2022/7/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85133129600&partnerID=8YFLogxK
U2 - 10.1038/s41586-022-04898-5
DO - 10.1038/s41586-022-04898-5
M3 - Article
C2 - 35768510
AN - SCOPUS:85133129600
SN - 0028-0836
VL - 607
SP - 593
EP - 603
JO - Nature
JF - Nature
IS - 7919
ER -