Mitochondrial Stress Provokes Inflammation via Fragments of Mitochondrial DNA
A large body of evidence links mitochondrial dysfunction with chronic inflammation. These are both features of aging, but it appears that dysfunctional, stressed mitochondria are a meaningful cause of inflammatory signaling. Mitochondria can generate molecular fragments, such as pieces of mitochondrial DNA, that are recognized as potentially threatening by the innate immune system. These damage-associated molecular patterns are present in much greater amounts in old tissues, and the immune system reacts to them to produce lasting, unresolved inflammation, harmful to tissue function rather than protective.
In today's research materials, scientists report on their investigation of how exactly it is that mitochondrial DNA fragments are ejected from cells to then provoke an immune response. Understanding the details of the processes involved may reveal points of intervention that can be used to suppress age-related chronic inflammation. The researchers here suggest FEN1 inhibition as a possibility, as this protein is involved in producing the fragments of DNA that then exit the cell to act as damage-associated molecular patterns.
How Mitochondrial Damage Ignites the "Auto-Inflammatory Fire"
When stressed, damaged or dysfunctional, mitochondria expel their DNA (mtDNA), oxidized and cleaved, into the cytosol - the fluid within a cell in which organelles float - and beyond into the bloodstream, triggering inflammation. In autoimmune conditions like lupus and rheumatoid arthritis, the amounts of circulating oxidized mtDNA correlate with disease severity, flare-ups, and how well patients respond to therapies. An unanswered question that has plagued the field is whether oxidized mtDNA is simply a biomarker or indicator of disease or something more: a critical player in disease pathology.
In a new study, researchers describe the biochemical pathway that results in the generation of oxidized mtDNA, how it is expelled by mitochondria and how it triggers the complex and destructive inflammatory response that follows. "In addition to charting a new pathway responsible for the generation of inflammation-provoking fragments of oxidized mtDNA, this work opens the door to the development of new anti-inflammatory agents."
Mitochondrial DNA (mtDNA) escaping stressed mitochondria provokes inflammation via cGAS-STING pathway activation and, when oxidized (Ox-mtDNA), it binds cytosolic NLRP3, thereby triggering inflammasome activation. However, it is unknown how and in which form Ox-mtDNA exits stressed mitochondria in non-apoptotic macrophages. We found that diverse NLRP3 inflammasome activators rapidly stimulated uniporter-mediated calcium uptake to open mitochondrial permeability transition pores (mPTP) and trigger VDAC oligomerization. This occurred independently of mtDNA or reactive oxygen species, which induce Ox-mtDNA generation.
Within mitochondria, Ox-mtDNA was either repaired by DNA glycosylase OGG1 or cleaved by the endonuclease FEN1 to 500-650 base pair fragments that exited mitochondria via mPTP- and VDAC-dependent channels to initiate cytosolic NLRP3 inflammasome activation. Ox-mtDNA fragments also activated cGAS-STING signaling and gave rise to pro-inflammatory extracellular DNA. Understanding this process will advance the development of potential treatments for chronic inflammatory diseases, exemplified by FEN1 inhibitors that suppressed interleukin-1β (IL-1β) production and mtDNA release in mice.