Mitochondrial RNA modifications shape metabolic plasticity in metastasis

Sylvain Delaunay, Gloria Pascual, Bohai Feng, Kevin Klann, Mikaela Behm, Agnes Hotz-Wagenblatt, Karsten Richter, Karim Zaoui, Esther Herpel, Christian Münch, Sabine Dietmann, Jochen Hess, Salvador Aznar Benitah and Michaela Frye ()
Additional contact information
Sylvain Delaunay: German Cancer Research Center – Deutsches Krebsforschungszentrum (DKFZ)
Gloria Pascual: The Barcelona Institute of Science and Technology (BIST)
Bohai Feng: University Hospital Heidelberg
Kevin Klann: Goethe University Frankfurt
Mikaela Behm: German Cancer Research Center – Deutsches Krebsforschungszentrum (DKFZ)
Agnes Hotz-Wagenblatt: German Cancer Research Center – Deutsches Krebsforschungszentrum (DKFZ)
Karsten Richter: German Cancer Research Center – Deutsches Krebsforschungszentrum (DKFZ)
Karim Zaoui: University Hospital Heidelberg
Esther Herpel: University Hospital Heidelberg
Christian Münch: Goethe University Frankfurt
Sabine Dietmann: Washington University School of Medicine in St. Louis
Jochen Hess: German Cancer Research Center – Deutsches Krebsforschungszentrum (DKFZ)
Salvador Aznar Benitah: The Barcelona Institute of Science and Technology (BIST)
Michaela Frye: German Cancer Research Center – Deutsches Krebsforschungszentrum (DKFZ)

Nature, 2022, vol. 607, issue 7919, 593-603

Abstract: 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.

Date: 2022
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-022-04898-5 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:607:y:2022:i:7919:d:10.1038_s41586-022-04898-5

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-04898-5

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().