mtDNA Activates cGAS Signaling and Suppresses the YAP-Mediated Endothelial Cell Proliferation Program to Promote Inflammatory Injury

Cytosolic DNA acts as a universal danger-associated molecular pattern (DAMP) signal; however, the mechanisms of self-DNA release into the cytosol and its role in inflammatory tissue injury are not well understood. We found that the internalized bacterial endotoxin lipopolysaccharide (LPS) activated the pore-forming protein Gasdermin D, which formed mitochondrial pores and induced mitochondrial DNA (mtDNA) release into the cytosol of endothelial cells. mtDNA was recognized by the DNA sensor cGAS and generated the second messenger cGAMP, which suppressed endothelial cell proliferation by downregulating YAP1 signaling. This indicated that the surviving endothelial cells in the penumbrium of the inflammatory injury were compromised in their regenerative capacity. In an experimental model of inflammatory lung injury, deletion of cGas in mice restored endothelial regeneration. The results suggest that targeting the endothelial Gasdermin D activated cGAS-YAP signaling pathway could serve as a potential strategy for restoring endothelial function after inflammatory injury. [Display omitted] •Activated Gasdermin D forms mitochondrial pores in the endothelium•Mitochondrial pore formation releases mitochondrial DNA into the cytosol•Released mtDNA activates cGAS signaling and suppresses vascular regeneration•Deletion of cGAS in an experimental model of polymicrobial sepsis reduces tissue injury Sepsis induces profound vascular injury by promoting endothelial cell death, but the role of mitochondria in vascular endothelial injury is not well understood. Huang et al. demonstrate that the pore-forming molecule Gasdermin D releases mitochondrial DNA into the cytosol, which sets into motion an amplified response resulting in suppression of endothelial regeneration mediated by the cytosolic DNA sensor cGAS.