A faulty DNA elimination system causes inflammation

Cells in the human body contain energy-generating mitochondria, each with its own mtDNA, a unique set of genetic instructions entirely distinct from the cell’s nuclear DNA that the mitochondria use to create life-sustaining energy. When mtDNA stays where it belongs (inside mitochondria), it maintains mitochondrial and cellular health, but when it goes where it doesn’t belong, it can trigger an immune response that promotes inflammation.

Now, Salk scientists and UC San Diego collaborators have discovered a new mechanism used to remove malfunctioning mtDNA from the inside to the outside of mitochondria. When this happens, the mtDNA is flagged as foreign DNA and activates a cellular pathway normally used to promote inflammation to rid the cell of pathogens, such as viruses.

The results, published in Natural cellular biologyoffer many new therapeutic targets to disrupt the inflammatory pathway and therefore attenuate inflammation linked to aging and diseases such as lupus or rheumatoid arthritis.

“We knew that mtDNA escaped from mitochondria, but it was still unclear how,” says senior and co-corresponding author Professor Gerald Shadel, director of the San Diego-Nathan Shock Center of Excellence in the Basic Biology of Aging and holder of the Audrey Geisel. Chair in biomedical sciences at Salk.

“Using imaging and cell biology approaches, we are able to trace the steps in the pathway for moving mtDNA out of the mitochondria, which we can now try to target with therapeutic interventions to hopefully , prevent the resulting inflammation.”

One of the ways our cells respond to damage and infection is through something called the innate immune system. Although the innate immune response is the first line of defense against viruses, it can also respond to molecules produced by the body that simply resemble pathogens, including misplaced mtDNA. This response can lead to chronic inflammation and contribute to human disease and aging.

Scientists worked to discover how mtDNA leaves the mitochondria and triggers the innate immune response, but previously characterized pathways did not apply to the unique mtDNA stress conditions that the Salk team was studying. So they turned to sophisticated imaging techniques to gather clues about where and when things went wrong in these mitochondria.

“We made a major breakthrough when we found that mtDNA was inside a mysterious membrane structure once it left the mitochondria. After putting all the pieces together, we realized that this structure was an endosome,” explains first author Laura Newman, a former postdoctoral researcher. in Shadel’s laboratory and current assistant professor at the University of Virginia.

“This discovery eventually led us to realize that mtDNA was being eliminated, and in doing so, some of it was escaping.”

The team discovered a process starting with a dysfunction in mtDNA replication that caused masses of mtDNA-containing proteins, called nucleoids, to build up inside mitochondria. Noticing this dysfunction, the cell then begins to remove the nucleoids that stop replication by transporting them to endosomes, a set of organelles that sort and send cellular material for permanent disposal.

The endosome becomes overloaded with these nucleoids, causes a leak, and the mtDNA suddenly sheds into the cell. The cell signals this mtDNA as foreign DNA – the same way it signals the DNA of a virus – and initiates the DNA-sensing cGAS-STING pathway to cause inflammation.

“By using our cutting-edge imaging tools to probe mitochondrial dynamics and mtDNA release, we have discovered an entirely new release mechanism for mtDNA,” says co-corresponding author Uri Manor, former director of the Waitt Advanced Biophotonics Core at Salk and current assistant professor. at UC San Diego.

“There are so many complementary questions we look forward to asking, such as how other interactions between organelles control innate immune pathways, how different cell types release mtDNA, and how we can target this new pathway to reduce inflammation during disease and aging.”

The researchers hope to further map this complex pathway of mtDNA elimination and immune activation, including the biological circumstances, such as mtDNA replication dysfunction and viral infection, that are necessary to initiate the pathway. and what downstream effects may have on human health. They also see an opportunity for therapeutic innovation using this pathway, which represents a new cellular target for reducing inflammation.