Kidney-derived mitochondrial extracellular vesicles trigger acute lung injury in sepsis via mtDNA-cGAS-STING in pulmonary endothelium

Sepsis often leads to multiple organ failure, but how injury in one organ propagates to another remains poorly understood. Here we show that the injured kidney releases mitochondria-rich extracellular vesicles (mitoEVs) into the circulation, which travel to the lung and trigger acute lung injury. In septic mice and cultured renal tubular epithelial cells, sepsis promotes the formation of mitochondrial-derived vesicles by upregulating sorting nexin 9. Blocking this process in kidney tubules reduces the release of mitoEVs and protects against lung injury. Once taken up by lung endothelial cells, the mitochondrial DNA carried by these vesicles activates an innate immune pathway involving cGAS and STING, with ZBP1 serving as a potential cooperative partner for this activation. This leads to endothelial barrier disruption, immune cell recruitment, and respiratory failure. In patients with sepsis, higher levels of circulating mitoEVs associate with lung injury and death. These findings identify a kidney-to-lung signaling axis that may be targeted therapeutically.