Mitochondria play a central role in innate immune responses, functioning as signaling platforms and contributing to effector responses. They regulate antiviral signaling, generate reactive oxygen species (ROS) for antibacterial immunity, and contribute to innate immune activation following cellular damage and stress. In addition to their roles in cellular metabolism and programmed cell death, mitochondria act as hubs in the innate immune system. The RLR family, including RIG-I, MDA5, and LGP2, is crucial for antiviral immunity. RLRs are expressed in the cytosol and are required for type I interferon (IFN) and pro-inflammatory cytokine production in response to viral infection. RIG-I and MDA5 possess CARDs for signaling, a DExD/H box RNA helicase domain for detecting viral RNA, and a C-terminal repressor domain. LGP2, initially thought to be a negative regulator, has been shown to positively regulate RIG-I and MDA5-dependent antiviral responses. MAVS is a key adaptor protein that interacts with RIG-I and MDA5, facilitating downstream NF-κB and IRF signaling. MAVS is localized to the outer mitochondrial membrane (OMM) and is essential for proper antiviral signaling. MAVS has three functional domains: an N-terminal CARD, a proline-rich region, and a C-terminal transmembrane segment. The CARD interacts with RIG-I and MDA5 CARDs, while the proline-rich region interacts with TRAF family members. The transmembrane domain facilitates MAVS dimerization and TRAF binding. MAVS signaling is regulated by various adaptor molecules, including TRAF2, TRAF3, TRAF6, TRADD, and TANK. These molecules interact with MAVS and facilitate NF-κB, IRF3, and IRF7 signaling. Additionally, WDR5 regulates MAVS signaling by facilitating the assembly of active MAVS signaling complexes on the mitochondrial surface. Mitochondrial cofactors, such as TOM70 and STING, are involved in MAVS signaling. TOM70 interacts with MAVS and is essential for antiviral responses. STING localizes to the OMM and ER membrane and is involved in RLR-MAVS signaling. STING interacts with RIG-I, MAVS, and TBK1, leading to IRF3 activation. Negative regulators of MAVS signaling include PCBP2 and gC1qR. PCBP2 recruits AIP4 to MAVS, leading to its degradation. gC1qR inhibits RLR-dependent NF-κB and IRF3 signaling by interacting with MAVS at the OMM. Mitochondrial dynamics, including fusion and fission, regulate RLR signaling. MFN2 interacts with MAVS and inhibits RLR signaling, while MFN1 is required for efficient RLR signaling. MitochondrialMitochondria play a central role in innate immune responses, functioning as signaling platforms and contributing to effector responses. They regulate antiviral signaling, generate reactive oxygen species (ROS) for antibacterial immunity, and contribute to innate immune activation following cellular damage and stress. In addition to their roles in cellular metabolism and programmed cell death, mitochondria act as hubs in the innate immune system. The RLR family, including RIG-I, MDA5, and LGP2, is crucial for antiviral immunity. RLRs are expressed in the cytosol and are required for type I interferon (IFN) and pro-inflammatory cytokine production in response to viral infection. RIG-I and MDA5 possess CARDs for signaling, a DExD/H box RNA helicase domain for detecting viral RNA, and a C-terminal repressor domain. LGP2, initially thought to be a negative regulator, has been shown to positively regulate RIG-I and MDA5-dependent antiviral responses. MAVS is a key adaptor protein that interacts with RIG-I and MDA5, facilitating downstream NF-κB and IRF signaling. MAVS is localized to the outer mitochondrial membrane (OMM) and is essential for proper antiviral signaling. MAVS has three functional domains: an N-terminal CARD, a proline-rich region, and a C-terminal transmembrane segment. The CARD interacts with RIG-I and MDA5 CARDs, while the proline-rich region interacts with TRAF family members. The transmembrane domain facilitates MAVS dimerization and TRAF binding. MAVS signaling is regulated by various adaptor molecules, including TRAF2, TRAF3, TRAF6, TRADD, and TANK. These molecules interact with MAVS and facilitate NF-κB, IRF3, and IRF7 signaling. Additionally, WDR5 regulates MAVS signaling by facilitating the assembly of active MAVS signaling complexes on the mitochondrial surface. Mitochondrial cofactors, such as TOM70 and STING, are involved in MAVS signaling. TOM70 interacts with MAVS and is essential for antiviral responses. STING localizes to the OMM and ER membrane and is involved in RLR-MAVS signaling. STING interacts with RIG-I, MAVS, and TBK1, leading to IRF3 activation. Negative regulators of MAVS signaling include PCBP2 and gC1qR. PCBP2 recruits AIP4 to MAVS, leading to its degradation. gC1qR inhibits RLR-dependent NF-κB and IRF3 signaling by interacting with MAVS at the OMM. Mitochondrial dynamics, including fusion and fission, regulate RLR signaling. MFN2 interacts with MAVS and inhibits RLR signaling, while MFN1 is required for efficient RLR signaling. Mitochondrial