PARKIN overexpression confers cardioprotection via suppressing the mtDNA-cGAS-STING axis in myocardial ischemia/reperfusion injury.

Abstract

Myocardial ischemia/reperfusion (I/R) injury is exacerbated by inflammation, yet the upstream triggers of this cascade and their amenability to therapeutic intervention remain unclear. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a driver of sterile inflammation in I/R injury, but whether its activation can be suppressed via enhanced mitochondrial quality control has not been explored. We hypothesized that augmenting PARKIN-mediated mitophagy would limit cGAS-STING activation and attenuate I/R injury by clearing damaged mitochondria and preventing the release of its agonist, mitochondrial DNA (mtDNA). Cardiomyocyte-specific PARKIN overexpression in mice was well tolerated at baseline and conferred cardioprotection following I/R injury, attenuating adverse remodeling and preserving cardiac function. Mechanistically, PARKIN overexpression enhanced mitophagy, which limited cytosolic mtDNA accumulation, thereby inhibiting cGAS-STING activation and its downstream inflammatory response. The therapeutic potential of this pathway was further supported by lentiviral PARKIN delivery in wild-type mouse hearts, which also improved cardiac outcomes following I/R injury. Taken together, our findings delineate a PARKIN-mtDNA-cGAS-STING axis as a regulatory mechanism of I/R injury and support PARKIN augmentation as a potential therapeutic strategy.