Mitochondrial nucleic acids in innate immunity and beyond

Mitochondria participate in a wide range of cellular processes. One essential function of mitochondria is to be a platform for antiviral signaling proteins during the innate immune response to viral infection. Recently, studies have revealed that mitochondrion-derived DNAs and RNAs are recognized as non-self molecules and act as immunogenic ligands. More importantly, the cytosolic release of these mitochondrial nucleic acids (mt-NAs) is closely associated with the pathogenesis of human diseases accompanying aberrant immune activation. The release of mitochondrial DNAs (mtDNAs) via BAX/BAK activation and/or VDAC1 oligomerization activates the innate immune response and inflammasome assembly. In addition, mitochondrial double-stranded RNAs (mt-dsRNAs) are sensed by pattern recognition receptors in the cytosol to induce type I interferon expression and initiate apoptotic programs. Notably, these cytosolic mt-NAs also mediate adipocyte differentiation and contribute to mitogenesis and mitochondrial thermogenesis. In this review, we summarize recent studies of innate immune signaling pathways regulated by mt-NAs, human diseases associated with mt-NAs, and the emerging physiological roles of mt-NAs. Mitochondria-derived DNAs and RNAs: the hidden triggers of innate immune response Mitochondrial nucleic acids (mt-NAs) play a crucial role in activating various innate immune signaling pathways and are associated with numerous human diseases. Downregulation of mt-NAs or their downstream receptors often alleviates interferon signature. Recent studies reveal that mt-NAs can also serve as key mediators of signaling between mitochondria and the nucleus, thereby contributing to cell physiology. In particular, studies have shown that mt-NAs can stimulate beige adipocyte development in young mice, which has potential therapeutic implications for obesity and insulin resistance. Understanding the multifaceted roles of mt-NAs will provide potential therapeutic strategies for mt-NA-mediated immune signaling regulation in pathophysiology. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.