First time: tRNA modifications in mitochondria shown to promote cancer metastasis
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First time: tRNA modifications in mitochondria shown to promote cancer metastasis.
Nature: For the first time, tRNA modification in mitochondria promotes cancer metastasis and spread
The mitochondria (mitochondrion)is the “energy factory” of the cell. There is a set of genetic material in the mitochondria that is independent of the nucleus – mitochondrial DNA (mtDNA).
The length of human mtDNA is 16569 bp, with 37 genes encoding 13 kinds of proteins. These proteins Both are involved in cellular energy metabolism.
Due to the important role of mitochondria in energy homeostasis, mitochondrial gene mutations can lead to a variety of diseases, including developmental disorders, neuromuscular diseases, cancer progression, and more.
On June 29, 2022, researchers from the German Cancer Research Center published a research paper entitled: Mitochondrial RNA modifications shape metabolic plasticity in metastasis in the top international academic journal Nature .
This study shows that m5C modification of mitochondrial tRNA mediated by methyltransferase NSUN3 can enhance energy supply by promoting protein synthesis in the mitochondrial respiratory chain, thereby promoting cancer cell invasion, proliferation and metastasis .
When blocking the NSUN3 enzyme, or using antibiotics to inhibit mitochondrial protein synthesis, the ability of cancer cells to invade and metastasize was significantly reduced.
In aggressive tumors, cancer cells continue to invade surrounding tissues and try to form new tumors in other tissues and organs.
During this process, cancer cells must survive under adverse conditions such as insufficient oxygen or nutrients. To overcome these stressors, cancer cells adjust their energy production accordingly.
Michaela Frye
However, until now, little was known about the molecular mechanisms by which cancer cells flexibly tune the way energy is produced.
This metabolic plasticity is likely key to the successful spread of cancer cells , says Michaela Frye , corresponding author of the paper .
Mitochondria are tiny , membrane-encapsulated organelles, also known as the power plants of every cell in our body.
Mitochondria generate energy through the respiratory chain located on its inner membrane.
Since mitochondria contain their own set of genetic material, mitochondrial DNA (mtDNA) , they are able to synthesize key protein components of the respiratory chain through mtDNA.
In this latest study, Michaela Frye ‘s team found that the production of respiratory chain components is tightly regulated by specific mechanisms in mitochondria, which have implications for the metastatic spread of cancer cells.
In the process of mRNA translation and protein synthesis, tRNA is responsible for transporting the corresponding amino acids to the ribosome to synthesize polypeptide chains.
The research team found that during metastasis, tRNA modifications regulate metastasis by supporting the production of proteins, that is, tRNA modifications are part of this cancer metastasis regulatory mechanism.
The invasion of cancer cells is actually a very energy-consuming process.
The research team found that a specific methylation modification of mitochondrial tRNA, m5C (5-methylcytosine) , is involved in the invasion and metastasis of cancer cells. required.
The m5C modification accelerates protein synthesis in mitochondria and enhances the production of respiratory chain components .
Thereby helping cancer cells to generate more capacity for consumption in the process of invasion and metastasis.
The research team found that m5C-modified cancer cells lacking mitochondrial tRNA produce energy inefficiently through glycolysis and have efficient transfer capabilities.
However, the viability and growth of cancer cells in primary tumors were not affected by m5C modification, which further confirmed that m5C modification of mitochondrial tRNA is responsible for the invasion and metastasis of cancer cells.
The methyltransferase NSUN3 , responsible for m5C RNA modification, the research team found that when the expression of NSUN3 enzyme was inhibited using RNAi (shRNA) , m5C modification of mitochondrial tRNA was significantly reduced, and the invasion and metastasis of cancer cells were reduced.
Metastasis of cancer cells requires m5C modification of mitochondrial tRNA
The research team further found that high expression of NSUN3 enzyme and elevated m5C modification could predict lymph node metastasis and more severe disease progression in patients with head and neck cancer.
This suggested to us that the NSUN3 enzyme has potential as a biomarker for metastatic cancer.
Some antibiotics (eg, chloramphenicol, doxycycline) specifically inhibit mitochondrial protein production without affecting cytoplasmic proteins.
The research team found that treatment with chloramphenicol or doxycycline reduced cancer cell invasion and metastasis, and also reduced the number of lymph node metastases in the mouse model.
Inhibition of mitochondrial protein synthesis with antibiotics inhibits cell metastasis
Finally, corresponding author Michaela Frye said that previous studies have explored the important role of mitochondrial RNA modifications in metabolic diseases, and this study is the first to demonstrate that mitochondrial tRNA modifications are directly related to cancer invasion and metastasis.
Inhibiting the NSUN3 enzyme responsible for RNA m5C modification may be a promising approach to blocking cancer metastasis, although further studies are needed to confirm whether there are long-term side effects of blocking mitochondrial protein synthesis in this way.
Paper link :
https://www.nature.com/articles/s41586-022-04898-5
First time: tRNA modifications in mitochondria shown to promote cancer metastasis
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