Towards Ways to Interfere in the Inflammatory Response to Mislocalized Mitochondrial DNA
Some fraction of the chronic inflammation of aging emerges because mitochondrial stress and dysfunction causes ejection of mitochondrial DNA fragments into the cell cytoplasm, where these fragments trigger the cGAS-STING pathway and consequent inflammatory signaling. Cells have evolved to be vigilant to misplaced DNA in large part because it is a marker of viral or bacterial infection. Obtaining a better understanding of the mechanisms involved in this process may identify points of intervention, ways to selectively suppress either the exposure of mitochondrial DNA in the cytoplasm or the reaction to that DNA when it is exposed.
While the innate immune response is the first line of defense against viruses, it can also respond to molecules the body makes that resemble pathogens - including misplaced mitochondrial DNA (mtDNA). This response can lead to chronic inflammation and contribute to human diseases and aging. Scientists have been working to uncover how mtDNA leaves mitochondria and triggers the innate immune response, but the previously characterized pathways did not apply to all mtDNA stress conditions. Researchers turned to sophisticated imaging techniques to gather clues as to where and when things were going awry in those mitochondria.
The team discovered a process beginning with a malfunction in mtDNA replication that caused mtDNA-containing protein masses called nucleoids to pile up inside of mitochondria. Noticing this malfunction, the cell then begins to remove the replication-halting nucleoids by transporting them to endosomes, a collection of organelles that sort and send cellular material for permanent removal. The endosome gets overloaded with these nucleoids, springs a leak, and mtDNA is suddenly loose in the cell. The cell flags that mtDNA as foreign DNA - the same way it flags a virus's DNA - and initiates the DNA-sensing cGAS-STING pathway to cause inflammation.
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.