Mitochondrial Dysfunction-Triggered Innate Immune Response and Its Therapeutic Implications

Mitochondria are essential organelles that play a pivotal role in a variety of biological processes, including energy production, metabolism, cell death, and inflammation. Interestingly, within these organelles lies a hidden component with the potential to activate the innate immune system: mitochondrial DNA (mtDNA). Pathogenic microorganisms invasion or danger signals can cause mitochondrial structures to become abnormal or dysfunctional, leading to the release of mtDNA into the cytoplasm, which in turn triggers the innate immune response. The leakage of mtDNA into the cytoplasm activates the cGAS-STING signaling pathway, which results in the production of type I interferons and inflammatory cytokines. Additionally, when mtDNA is oxidized, it can activate the NLRP3 inflammasome, leading to the initiation of various cell death mechanisms, such as pyroptosis. In this review, we delve into the role of mtDNA released from dysfunctional mitochondria as a potent activator of the immune system, which can lead to a cascade of inflammatory reactions. The engagement of the STING and NLRP3 inflammasomes is intricately linked to the development of inflammation, autoimmune disorders, and cancer. Targeting these pathways with specific agonists or inhibitors holds promise as a therapeutic strategy for a range of immune-related diseases and cancer.