A faulty DNA disposal system has been identified as the cause of inflammation in the human body, according to a recent study conducted by scientists at Salk Institute and UC San Diego. The study reveals that when mitochondrial DNA (mtDNA) is misplaced outside of mitochondria, it triggers an immune response that leads to inflammation.
Mitochondria are power-generating organelles found within cells. They contain their own set of genetic instructions, known as mtDNA, which is separate from the cell’s nuclear DNA. MtDNA is responsible for producing energy that is vital for the cell’s functioning. When mtDNA remains within the mitochondria, it supports mitochondrial and cellular health. However, if it escapes and ends up in other parts of the cell, it can initiate an immune response that promotes inflammation.
The research team used imaging and cell biology techniques to trace the pathway through which mtDNA moves out of the mitochondria. They found that when mtDNA is removed from the mitochondria, it is flagged as foreign DNA and activates a cellular pathway normally associated with inflammation. This pathway is usually used by cells to eliminate pathogens such as viruses.
The new findings, published in the journal Nature Cell Biology, provide valuable insights into potential targets for therapeutics to disrupt the inflammatory pathway. By targeting these specific pathways, it may be possible to mitigate inflammation associated with aging and diseases like lupus and rheumatoid arthritis.
Senior author Professor Gerald Shadel, director of the San Diego-Nathan Shock Center of Excellence in the Basic Biology of Aging, explains that while it was known that mtDNA was escaping mitochondria, the exact mechanism was unclear. The team’s discovery of the pathway for moving mtDNA out of the mitochondria opens up new possibilities for developing therapeutic interventions to prevent inflammation.
The improper response of the innate immune system, which is the body’s first line of defense against viruses and pathogens, can contribute to chronic inflammation and various diseases. When molecules that resemble pathogens, including misplaced mtDNA, are detected by the innate immune system, the inflammatory response is triggered.
Previous research had identified pathways through which mtDNA leaves mitochondria and activates the innate immune response. However, these pathways were not applicable to the unique stress conditions involving mtDNA that the Salk team was investigating. The researchers used advanced imaging techniques to investigate the mitochondria and uncover clues about the processes involved.
The team made a breakthrough when they observed that mtDNA was present within a membrane structure after leaving the mitochondria. This mysterious structure turned out to be an endosome—a collection of organelles responsible for sorting and eliminating cellular material. It was in this process of disposal that mtDNA was leaking out and triggering the immune response.
The study revealed that a malfunction in mtDNA replication leads to the accumulation of mtDNA-containing protein masses called nucleoids inside the mitochondria. The cell then removes these dysfunctional nucleoids by transporting them to the endosome. However, as the endosome becomes overloaded with nucleoids, it leaks, causing mtDNA to be released into the cell. The cell recognizes the mtDNA as foreign and initiates an inflammatory response through the DNA-sensing cGAS-STING pathway.
Understanding how mtDNA causes inflammation provides new opportunities for developing interventions to target and disrupt the inflammatory pathway. This could ultimately lead to the development of therapeutics that mitigate inflammation associated with aging and various diseases, improving overall health and well-being.
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1. Source: Coherent Market Insights, Public sources, Desk research
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