Mitochondria, beyond their role in energy production, are involved in immune responses by releasing mitochondrial DNA (mtDNA), which acts as a damage-associated molecular pattern (DAMP). mtDNA activates innate immune pathways such as TLR9, NLRP3 inflammasome, and cGAS-STING. These pathways are interconnected and contribute to inflammatory diseases. mtDNA is released under stress conditions, triggering immune responses through various mechanisms, including TLR9 activation, NLRP3 inflammasome activation, and cGAS-STING signaling. TLR9 recognizes mtDNA and activates downstream signaling, leading to inflammatory responses. NLRP3 inflammasome activation by mtDNA leads to the release of pro-inflammatory cytokines. The cGAS-STING pathway detects mtDNA and activates interferon responses. The crosstalk between these pathways is complex and involves multiple interactions. Other factors, such as Mn²⁺, also contribute to innate immune activation. Understanding these pathways is crucial for developing therapeutic strategies for inflammatory diseases.Mitochondria, beyond their role in energy production, are involved in immune responses by releasing mitochondrial DNA (mtDNA), which acts as a damage-associated molecular pattern (DAMP). mtDNA activates innate immune pathways such as TLR9, NLRP3 inflammasome, and cGAS-STING. These pathways are interconnected and contribute to inflammatory diseases. mtDNA is released under stress conditions, triggering immune responses through various mechanisms, including TLR9 activation, NLRP3 inflammasome activation, and cGAS-STING signaling. TLR9 recognizes mtDNA and activates downstream signaling, leading to inflammatory responses. NLRP3 inflammasome activation by mtDNA leads to the release of pro-inflammatory cytokines. The cGAS-STING pathway detects mtDNA and activates interferon responses. The crosstalk between these pathways is complex and involves multiple interactions. Other factors, such as Mn²⁺, also contribute to innate immune activation. Understanding these pathways is crucial for developing therapeutic strategies for inflammatory diseases.