Figure 1.

The schematic diagram of mtDNA-releasing and sensing pathways mediating injury in lung tissue. In cell injury or infection conditions, abnormal mtDNA can be released from mitochondria into cytosol through mPTP, GSDMD pore, MOMP mediated by BAX/BAK and VDAC, or from cytosol to extracellular environment by EVs. Once in the cytosol, mtDNA, which comes from intracellular injured mitochondria or extracellular space, can be recognized by three major sensors that drive the innate immune response. First, the released mtDNA can bind to TLR9 on the surface of erythrocytes to induce an immune response or bind to TLR9 in the endosome, which promotes the expression of downstream NF-κB or p38 MAPK, leading to an upregulation of pro-inflammatory factor expression. Cytoplasmic mtDNA is also recognized by cGAS and leads to increased expression of cytokines, adhesion molecules, and chemokines through different pathways and can inhibit autophagy and endothelial cell proliferation. In addition, the released mtDNA activates PRRs such as NLRP3 and AIM2, recruiting ASC and procaspase-1 to form inflammasomes and promoting IL-1β and IL-18 maturation and pyroptosis.