Researchers from the Max Planck Institute for Biology of Aging and the CECAD have examined the immune reactions in various yeast strains and found out why mitochondria release their genetic material and thus trigger an inflammatory reaction. The reason is too low a concentration of pyrimidines, special DNA building blocks, inside the cell. These findings from Prof. Dr. Thomas Langer and his team can now be read in Nature Metabolism.
The mitochondria of our cells have their own genetic material in the form of DNA. They are not only significantly involved in the energy metabolism, but also trigger inflammatory reactions, for example, when the mitochondrial DNA is released into the cell interior. The first authors Hans-Georg Sprenger and Thomas MacVicar and their colleagues have now investigated the exact conditions under which mitochondria release their genetic material into the cell.
The protein YME1L (yeast mitochondrial escape 1) plays a crucial role here. It promotes the synthesis of DNA building blocks and switches off a transport protein, SLC25A33, which transports pyrimidines from the inside of the cell to mitochondria. In the presence of YME1L, more pyrimidines are available for cell metabolism outside the mitochondria. The researchers knocked out the YME1L gene in a yeast strain in order to analyze more precisely why this led to an inflammatory reaction. They found that in the absence of YME1L, mitochondrial DNA is released, causing an inflammatory response. The same effect can also be triggered by stimulating the yeast cells to produce large amounts of SLC25A33, which means that fewer pyrimidines are available inside the cell. Similarly, mitochondrial DNA-induced inflammation was found if the synthesis of new pyrimidine molecules was prevented by genetic changes, even if YME1L was present.
Regardless of the cause, a pyrimidine deficiency in the cell initially stimulates the mitochondria to give up their genetic material before an inflammatory reaction is triggered. The biologists were able to counteract this process by adding pyrimidines to the yeast cells in the nutrient medium.
Inflammatory reactions play a role in classic age-related diseases such as heart and neurodegenerative diseases. The researchers hope that the now elucidated inflammatory metabolic pathway can be used to find new target to develop therapies.
Further information can be found in the press release of the Max Planck Institute for Biology of Aging under the following link: https://www.age.mpg.de/communications/news/detail/dna-building-blocks-regulate-inflammation
Original publication:
Hans-Georg Sprenger *, Thomas MacVicar *, Amir Bahat, Kai Uwe Fiedler, Steffen Hermans, Denise Ehrentraut, Katharina Ried, Dusanka Milenkovic, Nina Bonekamp, Nils-Göran Larsson, Hendrik Nolte, Patrick Giavalisco und Thomas Langer. Cellular nucleotide imbalance triggers mitochondrial DNA-dependent innate immunity.
Nature Metabolism. 2021
* shared first authorship