Fig. 5.

Innate immune response pathways elicited by damage-associated molecular patterns (DAMPs). Mitochondrial stress or Bak/Bax-driven OMM permeabilization can lead to release of mtDNA or dsRNA into the cytosol, triggering a cascade that results in activated expression of type I interferon and pro-inflammatory cytokine genes. Cytosolic mtDNA can bind the DNA-sensing protein cGAS that catalyzes the production of 2′3′-cyclic GMP-AMP (cGAMP), which in turn binds the adaptor molecule STING1 on the ER, activating TBK1. TBK1 phosphorylates and thus induces the translocation of the transcription factor IRF3 into the nucleus, where it activates type I interferon genes. mtDNA can also trigger a pro-inflammatory or type I interferon response via binding to Toll-like receptor 9 (TLR9) located on endosomes. In addition, mtDNA can be an endogenous agonist of cytosolic inflammasomes, multi-subunit complexes consisting of the receptor NLRP3 (or NLRC4, or AIM2), the adaptor ASC and the inflammatory cysteine protease caspase-1, which processes pro-IL-1β and pro-IL-18 into their mature forms. Double-stranded RNA (dsRNA) is recognized by the retinoic acid-inducible gene-I-like receptors (RLRs) RIG-I or melanoma differentiation-associated gene 5 (MDA5), which bind to mitochondrial antiviral signaling protein (MAVS) through homotypic caspase activation and recruitment domain (CARD)-CARD interactions. MAVS then recruits various molecules to transduce a downstream signal to the nucleus, resulting in the activation of target genes. ER, endoplasmic reticulum; IFN, interferon; ISG, interferon-stimulatory gene; mtROS, mitochondrial reactive oxygen species.