Autophagy deficiency exacerbated hypoxia-reoxygenation induced inflammation and cell death via a mitochondrial DNA/STING/IRF3 pathway

• Published in: Life sciences (1973) 2024-12, Vol.358, p.123173, Article 123173
• Main Authors: Tam, Eddie, Song, Erfei, Noskovicova, Nina, Hinz, Boris, Xu, Aimin, Sweeney, Gary
• Format: Article
• Language: English
• Subjects: Animals; Atg7; Autophagy; Autophagy-Related Protein 7 - deficiency; Autophagy-Related Protein 7 - genetics; Autophagy-Related Protein 7 - metabolism; cardiomyocytes; Cell Death; Cell Line; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; gene expression; Heart; homeostasis; Hypoxia; inflammation; Inflammation - metabolism; Inflammation - pathology; Interferon Regulatory Factor-3 - metabolism; ischemia; Male; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; mitochondria; mitochondrial DNA; Mitophagy; Myocardial Reperfusion Injury - genetics; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Rats; Reoxygenation; Signal Transduction; therapeutics
• ISSN: 0024-3205; 1879-0631; 1879-0631
• DOI: 10.1016/j.lfs.2024.123173

Autophagy is an important cellular process for maintaining physiological homeostasis and is known to protect against cardiovascular diseases including ischemia reperfusion (I/R) injury. The underlying mechanisms behind its protection require further characterization. Atg7 knock out (AKO) mice were generated and subjected to I/R injury, complemented by Atg7 KO in a H9c2 cardiomyoblast cellular model ± hypoxia-reoxygenation. Subsequently, in both models, inflammation and cell death were studied. We confirmed that Atg7 KO led to autophagy, including mitophagy, deficiency. Upon H/R, Atg7 KO cells exhibited increased cell death compared to WT cells. Notably, we found that autophagy deficiency increased stress-induced mitochondrial fission, release of mitochondrial DNA, and sterile inflammation, namely activation of a STING/IRF3 axis leading to elevated interferon-α. Following I/R injury, AKO mice showed elevated cell death which correlated with a gene expression profile indicative of decreased anti-inflammatory responses. Autophagy deficiency in the cardiomyocyte setting results in detrimental effects during I/R injury in mice or H/R injury in cells, mediated in part via mtDNA/IRF3/STING pathway. As such, modulation of this pathway may yield novel and promising therapeutics to treat or prevent I/R injury.