Mitochondria are at the center of three inflammatory mechanisms: the NLRP3 inflammasome, cGAS/STING pathway, and NF-κB pathway. NLRP3 inflammasome activation is considered a two-step process: First, priming requires activation of NF-κB by PAMPs or DAMPs binding to pattern recognition receptors including TLRs or by cytokines, such as TNF-α or IL-1β, via their receptors. NF-κB stimulates the transcription and posttranslational stabilization of inactive forms of NLRP3, precursors of cytokines pro–IL-1β and pro–IL-18, and other NF-κB–related cytokines such as IL-6. Second, during activation, a multitude of DAMPs, such as ATP, cholesterol crystals, and urate crystals, promote inflammasome assembly, involving NIMA-related kinase 7 (NEK7), a sensor of K⁺ efflux (180). The activation likely requires K⁺ efflux, ROS production, and relocalization of cardiolipin to the outer mitochondrial membrane. It has been proposed that all stimuli that trigger the NRLP3 inflammasome converge on mitochondria, possibly via release of newly synthesized oxidized mtDNA, but K⁺ efflux may also be critical (181, 182). NLRP3 activation causes activation of caspase-1 and cleavage of pro–IL-1β and pro–IL-18 to their activated forms. Caspase-1 also cleaves gasdermin D (GSDMD), which oligomerizes to form pores in the cell membrane, which may lead to extracellular release of IL-1 and IL-18, K⁺ efflux, and massive swelling with membrane rupture (pyroptosis). The DNA sensor cGAS binds to mtDNA released into the cytosol and catalyzes production of the secondary messenger cyclic GMP-AMP (cGAMP) from ATP and GTP. cAGMP binds to the ER membrane adaptor STING, which is displaced to the perinuclear endosome and activates TANK binding kinase 1 (TBK1), which, in turn, phosphorylates interferon regulatory factor 3 (IRF3) that enters the nucleus and enhances transcription of type I IFN and IFN-stimulated genes (ISGs), while also activating NF-κB. In cell culture, cGAS overexpression induces IFN-β, whereas cGAS knockdown erases IFN-β induction by DNA transfection (183). cGAS/STING activation also enhances autophagy (184) and induces cellular senescence (185). NF-κB is activated by diverse stress signals and pathways related to defense and survival (89, 186). Multiple stress signals activate the NF-κB dimer (composed of p65/p50 subunits) that translocates to the nucleus, where it binds to consensus sequences in regulatory regions of target genes (187). NF-κB activation drives multiple pleiotropic effects, including enhancing the transcription of proinflammatory mediators, such as TNF-α and IL-6, that regulate both innate and adaptive immunity (95). CARD, caspase recruitment domain; GSDMD^Nterm, GSDMD amino-terminal cell death domain; LRR, leucine-rich repeat; PYD, pyrin domain.