RNA modifications in mitochondria promote invasive spread of cancer

Mitochondria are the power plants of cells, and they contain their own genetic material and RNA molecules. Scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now discovered that certain modifications in mitochondrial RNA boost the invasive spread of cancer cells by supporting protein synthesis in mitochondria. They have established that a specific gene expression signature correlating with high levels of mitochondrial RNA modifications is associated with metastasis and poor prognosis in patients with head and neck cancer. When the researchers blocked the responsible RNA modifying enzyme in cancer cells, the number of metastases was reduced. Certain antibiotics that suppress protein synthesis in mitochondria were also able to prevent the invasive spread of cancer cells in laboratory experiments. The results have now been published in the journal Nature.

Cancer cells in aggressive tumours invade the surrounding tissue in an attempt to form a new tumour in other organs. During this journey, cancer cells have to survive unfavourable conditions such as shortage of oxygen or shortage in nutrients. To overcome these stress factors, cancer cells adapt their energy production accordingly. The molecular mechanisms allowing this flexibility were poorly understood until now. “However, we suspected that this metabolic plasticity must be a key to the successful spread of the cancer cells,” says Michaela Frye; cell biologist at the German Cancer Research Center.

Mitochondria are tiny, membrane-enveloped structures known as the powerhouse of every cell in our body. For energy production, they use the so-called respiratory chain present in the mitochondrial membrane. Because mitochondria contain their own genetic material, they themselves produce key components of the respiratory chain.

The production of components of the respiratory chain is tightly regulated by a specific machinery in the mitochondria — with implications for the metastatic spread of cancer cells, as Michael Frye and her team have now discovered and published in the journal Nature. tRNA molecules are part of this machinery and are responsible for providing the individual amino acid building blocks during protein assembly. The research team identified the deposition of molecular modifications on mitochondrial tRNAs as the control mechanism to support production of proteins during metastasis.

RNA modifications regulate mitochondrial function and drive metastasis

Cancer cell invasion is a very energy consuming process. The team in Heidelberg discovered that a specific chemical modification found in mitochondrial tRNA, known as “m5C” (5-methylcytosine), is required for metastasis development. The m5C modification cranks up protein synthesis in the mitochondria. This enhances the production of components of the respiratory chain. As a result, the cell increases its pool of energy to fuel demanding cellular processes such as cancer cell dissemination from the tumour.

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