Figure 7.

Mitochondrial-mediated immune functions and cell signaling. Under conditions of stress, mitochondria can release molecules such as N-formyl peptides, ROS, mtDNA, and cardiolipin. These components can initiate an immune response and related signaling pathways in the cytosol or extracellular space. N-Formyl peptides are released and act as chemoattractants for neutrophils, binding to the formyl peptide receptor 1 (FPR-1) and promoting their activation and release of pro-inflammatory cytokines including TNFα, IL-1β, and IFNγ. Cardiolipin translocates from the inner to the outer mitochondrial membrane, where it interacts with the nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR)-containing protein (NLR)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. ROS activates mitochondrial anti-viral signaling (MAVS) protein located on the outer membrane, triggering activation of the NF-κB pathway and the release of interferon-regulating factors (IRFs). Additionally, MAVS can promote the oligomerization and activation of the NLRP3 inflammasome. MtDNA fragments (or components containing mtDNA, e.g., mtDNA nucleoids) released from the organelle bind TLR9 receptors that activate NF-κB signaling or, in the cytosol, initiate cyclic GMP/AMP synthase—stimulator of interferon genes (cGAS–STING) pathways that potentiate interferon responses. Individually or collectively, these mitochondrial-initiated processes mediate a cascade of pro-inflammatory pathways and cytokines that contribute to innate immune response.