Hidden cause of inflammation
Excess RNA building blocks destabilize mitochondrial DNA
In mice, inflammation caused by a deficiency of DNA building blocks leads to scarring in the glomeruli of the kidneys.
© MPI f. Biology of Ageing
To the point
- Chronic inflammation in old age: Mitochondrial DNA instability identified as trigger.
- Excess RNA building blocks: An excess of ribonucleotides leads to faulty incorporation into mitochondrial DNA.
- Further research: Can the administration of DNA building blocks reduce age-related inflammatory reactions?
Chronic inflammation increases with age. One trigger for this is found in the mitochondria, which supply energy to cells. These organelles have their own DNA, which induces an inflammatory reaction when it leaks from the mitochondria. In a study, researchers at the Max Planck Institute for Biology of Ageing showed that an imbalance of nucleotides — the building blocks of DNA and RNA — is responsible for this. If there are too little DNA building blocks in the cell, RNA building blocks are incorrectly incorporated into the mitochondrial DNA. This renders the DNA unstable and causes it to be released from mitochondria. These findings significantly advance our understanding of age-related inflammation.
Our bodies need energy, which is provided by the mitochondria in our cells. Unlike other cell components, mitochondria have their own DNA, called mitochondrial DNA. Once this DNA is released from mitochondria, it activates the cell's own immune system and triggers an inflammatory response. This reaction occurs more frequently with increasing age and in senescent cells, which contribute significantly to aging. Mitochondria absorb the building blocks for their DNA from inside the cell. The research team led by Thomas Langer had already shown that a deficiency of DNA building blocks in the cell can cause the release of mitochondrial DNA. However, the exact mechanism was previously unknown.
RNA building blocks incorporated into mitochondrial DNA
The researchers have now discovered that an excess of RNA building blocks (ribonucleotides) causes them to be incorrectly incorporated into mitochondrial DNA. This makes the mitochondrial DNA unstable, causing it to escape from the mitochondria into the cell interior. The researchers observed this instability in both aged tissue and senescent cells. By replenishing DNA building blocks they were able to compensate for this effect and prevent the inflammatory response. Mitochondria are particularly susceptible to an imbalance of DNA and RNA building blocks because, unlike the nuclear DNA replication in the cell nucleus, they do not have a repair mechanism that removes the incorrectly incorporated RNA building blocks.
The researchers were also able to show that an excess of RNA building blocks can contribute to inflammation using a mouse model. These mice developed kidney inflammation and died sooner. 'There is already a therapy for certain mitochondrial diseases that involves administering DNA building blocks. However, we do not yet know if it can also alleviate the inflammation that occurs more frequently with age. It would be interesting to test this," says Dusanka Milenkovic, one of the study's lead authors. "Our findings explain on a molecular level how metabolic disturbances can lead to inflammation in senescent cells and in aged tissue and open up new strategies for possible interventions.," adds Thomas Langer, who led the study.