FIG. 3.

Released mtDNA activates TLR9 and inflammasome. (A) MtDNA can be released to the cytosol or extracellular space when cells receive various stresses, including mechanical stress or infection. Released mtDNA activates the TLR9-mediated signaling pathway in immune cells such as neutrophils and initiates the proinflammatory cascade to produce proinflammatory cytokines. Extracellular mtDNA also causes adherence of neutrophils and endothelial cells by activating their adherence molecules (e.g., ICAM1 or e-selectin in endothelial cells; CD18 or L-selectin in neutrophils). These events result in systemic endothelia permeability. (B) In the normal condition, aged or damaged mitochondria in cells are eliminated by the autophagy machinery, called mitophagy, to avoid excess generation of oxidative stress. However, when autophagy (mitophagy) is inhibited or the number of damaged mitochondria is beyond the capacity of the autophagy machinery, mtDNA is released into the cytosol. The cytosolic mtDNA activates NLRP3 inflammasome-mediated caspase-1 activation, leading to the secretion of IL-1β and IL-18. Cytosolic mtDNA can also activate AIM2-dependent inflammasome. AIM2, absent in melanoma 2; ICAM1, intercellular adhesion molecule 1; IL-1β, interleukin-1 beta; mtDNA, mitochondrial DNA. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars