Mechanistic review reveals mitochondrial DNA drives necroptosis and pyroptosis in failing hearts, indicating novel therapeutic targets.
Key Points
To delineate how released mitochondrial DNA acts as a damage-associated molecular pattern to trigger programmed necrotic cell death pathways in failing hearts.
Reviewed mechanistic evidence linking mitochondrial injury and mitochondrial DNA (mtDNA) release to heart failure pathogenesis.
Analyzed downstream activation of nucleic acid sensors and pro-inflammatory pathways, including ZBP1-RIP3-MLKL, cGAS-STING, and NLRP3/AIM2 inflammasomes.
Cytosolic mtDNA activates the ZBP1-RIP3-MLKL axis to drive necroptosis and stimulates cGAS-STING signaling to produce pro-necroptotic cytokines.
Extracellular and cytosolic mtDNA engages NLRP3 and AIM2 inflammasomes, triggering pyroptosis and amplifying myocardial inflammation.
Circulating mtDNA correlates with heart failure severity, supporting mtDNA-targeted interventions and sensor inhibitors as viable therapeutic strategies.