Scientists Uncover Mechanism for Mitochondrial DNA Escape

Cells in the human body contain mitochondria, which generate energy through mtDNA, separate from nuclear DNA. When mtDNA escapes mitochondria, it triggers an immune response causing inflammation. Scientists at Salk and UC San Diego have discovered a mechanism used to remove malfunctioning mtDNA from mitochondria, which triggers an inflammatory response similar to that against pathogens. Published in Nature Cell Biology, this discovery offers potential targets for therapeutics to mitigate inflammation in conditions like lupus or rheumatoid arthritis.

“We knew that mtDNA was escaping mitochondria, but how was still unclear,” says senior author Gerald Shadel. “Using imaging and cell biology approaches, we’re able to trace the steps of the pathway for moving mtDNA out of the mitochondria.”

"We had a huge breakthrough when we saw that mtDNA was inside of a mysterious membrane structure once it left mitochondria—after assembling all of the puzzle pieces, we realized that structure was an endosome,” says first author Laura Newman. “That discovery eventually led us to the realization that the mtDNA was being disposed of and, in the process, some of it was leaking out.”

The team found that malfunctioning mtDNA replication leads to nucleoid accumulation, which is then transported to endosomes for disposal. Overloading of endosomes leads to mtDNA leakage, triggering inflammation through the cGAS-STING pathway.

Next the researchers hope to map out more of this complicated mtDNA-disposal and immune-activation pathway, including what biological circumstances—like mtDNA replication dysfunction and viral infection—are required to initiate the pathway and what downstream effects there may be on human health. They also see an opportunity for therapeutic innovation using this pathway, which represents a new cellular target to reduce inflammation.