Mitochondrial RNA modifications shape metabolic plasticity in metastasis

Area of Science:

• Molecular Biology
• Cancer Research
• Metabolic Plasticity

Background:

• Metastatic cancers exhibit enhanced metabolic plasticity, but the mechanisms are not fully understood.
• RNA modifications play crucial roles in cellular processes, including gene expression.

Purpose of the Study:

• To investigate the role of NOP2/Sun RNA methyltransferase 3 (NSUN3)-dependent RNA modifications in driving cancer metastasis.
• To elucidate the mechanisms by which mitochondrial mRNA translation fuels cancer cell invasion and dissemination.

Main Methods:

• Analysis of 5-methylcytosine (m5C) and 5-formylcytosine (f5C) modifications in mitochondrial tRNA.
• Assessment of cancer cell viability, glycolysis, mitochondrial function, and metastasis in m5C-deficient cells.
• Identification of a mitochondria-driven gene signature in head and neck cancer patients.

Main Results:

• NSUN3-dependent m5C modification at position 34 in mitochondrial tRNA is essential for oxidative phosphorylation and metastasis.
• m5C-deficient oral cancer cells show impaired metabolic plasticity and reduced metastasis, despite normal primary tumor growth.
• CD36-dependent tumor cells require mitochondrial m5C for invasion and dissemination.
• A mitochondria-driven gene signature predicts metastasis and progression in head and neck cancer.

Conclusions:

• Mitochondrial RNA modifications, specifically m5C, are critical regulators of cancer cell metabolic plasticity and metastasis.
• Targeting mitochondrial mRNA translation presents a potential therapeutic strategy to inhibit cancer metastasis.