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

Aims: 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.
Materials and Methods: 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.
Key Findings: 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.
Significance: 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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gary Sweeney reports financial support was provided by the Heart & Stroke Foundation of Canada. Gary Sweeney reports a relationship with Allysta Pharmaceuticals Inc. that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)