Every cell contains hundreds of mitochondria, each with its own genome, mitochondrial DNA separate from that of the cell nucleus. The primary role of mitochondria is to generate chemical energy store molecules, adenosine triphosphate (ATP), used to power cell activities. Mitochondrial dysfunction with aging isn't just a loss of ATP generation and production of a harmful amount of reactive oxygen species, however. It can also be connected with chronic inflammation, as mislocalization of mitochondrial DNA can trigger sensors of the innate immune system to provide inflammatory signaling. Mitochondria are the descendants of ancient symbiotic bacteria, and there is a certain degree of overlap in the evolved mechanisms that detect the presence of bacteria and those that detect cellular damage and dysfunction. This is all the more reason for a greater focus on the development of ways to reverse the mitochondrial dysfunction observed in older individuals.
In addition to constituting the genetic material of an organism, DNA is a tracer for the recognition of foreign pathogens and a trigger of the innate immune system. cGAS functions as a sensor of double-stranded DNA fragments and initiates an immune response via the adaptor protein STING. The cGAS-STING pathway not only defends cells against various DNA-containing pathogens but also modulates many pathological processes caused by the immune response to the ectopic localization of self-DNA, such as cytosolic mitochondrial DNA (mtDNA) and extranuclear chromatin.
In addition, macrophages can cause inflammation by forming a class of protein complexes called inflammasomes, and the activation of the NLRP3 inflammasome requires the release of oxidized mtDNA. In innate immunity related to inflammasomes, mtDNA release is mediated by macropores that are formed on the outer membrane of mitochondria via VDAC oligomerization. These macropores are specifically formed in response to mitochondrial stress and tissue damage, and the inhibition of VDAC oligomerization mitigates this inflammatory response. The rapidly expanding area of research on the mechanisms by which mtDNA is released and triggers inflammation has revealed new treatment strategies not only for inflammation but also, surprisingly, for neurodegenerative diseases such as amyotrophic lateral sclerosis.