Mitochondrial DNA : A Key Alarmin Igniting the Inflammasome Fire in Health and Disease

ABSTRACT Beyond their classical role as cellular powerhouses, mitochondria are now recognised as indispensable hubs for innate immune signalling. A pivotal aspect of this function is the release of mitochondrial DNA (mtDNA), a potent damage‐associated molecular pattern (DAMP) that, when misplaced, acts as a powerful alarmin due to its prokaryotic origins. In response to cellular stress or infection, mtDNA translocates to the cytosol and activates intracellular protein platforms known as inflammasomes, triggering the maturation of cytokines like interleukin‐1β (IL‐1β) and inducing a lytic form of cell death, pyroptosis. This review synthesises current research on this intricate relationship. Whilst potassium (K + ) efflux remains the canonical trigger for the NLR family pyrin domain containing 3 (NLRP3) inflammasome, emerging and debated roles of oxidised mtDNA (ox‐mtDNA) as a potential direct ligand or critical upstream amplifier are explored. The manuscript elucidates mtDNA release mechanisms, such as mitochondrial permeability transition pore (mPTP) opening, and explores the role of amplifying pathways like the cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) axis and cytidine/uridine monophosphate kinase 2 (CMPK2)‐mediated mtDNA synthesis. The profound involvement of the mtDNA‐inflammasome axis is surveyed across a spectrum of pathologies, including autoimmune, metabolic, neurodegenerative, and cardiovascular diseases. The compiled evidence establishes mtDNA as a universal trigger of inflammation and a unifying pathogenic driver across this diverse disease landscape, highlighting the significant therapeutic potential of modulating this fundamental immune signalling axis to treat a multitude of human diseases.