Figure 2. Mitochondrial nucleic acid cytosolic release drives inflammatory signaling in aging and neurological disease.

Mitochondrial dysfunction can promote the release of mtDNA and mt-dsRNA into the cytosol, where these nucleic acids engage innate immune signaling pathways. Cytosolic mtDNA activates cGAS–STING signaling, whereas cytosolic mt-dsRNA activates the RNA sensors RIG-I and MDA5, ultimately promoting activation of inflammatory transcription factors and neuroinflammatory gene programs. Altered PINK1 signaling and SEC61A1-mediated mitochondrial–endoplasmic reticulum interactions have been implicated in mitochondrial nucleic acid release. These pathways are increasingly associated with aging and neurological disorders, highlighting mitochondrial nucleic acid leakage as a potential mechanism linking mitochondrial dysfunction to neuroinflammation. ER: endoplasmic reticulum