Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance

Mitochondria, in addition to their classic role in energy production, have emerged as central hubs in the regulation of innate immunity. Under conditions of cellular stress, mitochondrial dysfunction triggers the release of mitochondrial DNA (mtDNA) into the cytosol or extracellular space, activating potent inflammatory pathways such as cGAS-STING, NLRP3 and TLR9. mtDNA release, driven by factors such as oxidative damage, membrane permeabilization, and various cell death pathways, is involved in immune surveillance and the pathogenesis of various diseases. At the same time, this downstream event leads to profound reorganization of immune cell metabolism, influencing functional polarization and inflammatory outcomes. This review presents the mitochondrion as an interface between metabolism, immunity, immunometabolites, and danger signalling. We explore the molecular mechanisms of mtDNA release, its conversion into immune signals, and its impact on metabolism in immune cells. Translational implications for pathologies such as neurodegenerative, autoimmune, and neoplastic diseases are also discussed. Deciphering the interconnection between mitochondrial stress, mtDNA release, and immunometabolic rewiring could open new avenues for the treatment of complex diseases and drive innovation in immunotherapy and regenerative medicine.