FIGURE 2.

Mitochondria involvement in innate immune responses in macrophage/microglia. Damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) can be recognized by pattern recognition receptors (PRRs) to cause mitochondrial damage, which leads to increased mitochondrial reactive oxygen species (mtROS) formation, mitochondrial DNA (mtDNA) release, and decreased ATP generation. Cyclic guanosine monophosphate-adenylate synthetase (cGAS) is a cellular DNA sensor that primarily recognizes double-stranded DNA, i.e., mtDNA, using ATP and GTP as substrates to produce the second messenger cGAMP, which then binds to and trigger stimulator of interferon genes (STING) oligomerization. Activated STING recruits TBK1 and activate downstream IRF3, IRF7, or nuclear factor-κB (NF-κB), ultimately inducing the expressions of type-I interferons (IFNs) and proinflammatory cytokines. Also, mtDNA and mtROS are canonical activators of the NLRP3 inflammasome and IL-1β secretion. Additionally, mitochondrial antiviral signaling (MAVS) protein is a RIG-like receptor (RLR) localized on the OMM. mtROS accumulation potentiates the MAVS downstream cascade, which also contributes to activations of NF-κB, IRF3, and IRF7, leading to a pronounced generation of cytokines and IFNs. Collectively, damaged mitochondria serve as hubs of multiple signaling cascades in facilitating innate immune responses in macrophages and microglia.