Exosome-derived mtDNA disrupts endothelial barrier integrity and accelerates sepsis progression by inducing...

Sepsis, a severe inflammatory response to infection, is characterized by complex and rapidly evolving pathophysiology with high mortality. Mitochondrial DNA (mtDNA) in exosomes is a key damage-associated molecular pattern implicated in sepsis; however, its exact role and mechanisms are unclear. This study investigates how exosome-derived mtDNA induces mitochondrial dysfunction via protein kinase C delta (PKCδ), leading to endothelial barrier disruption and the progression of sepsis. Our analysis revealed significantly elevated levels of the mtDNA markers ND2 and D-loop in serum exosomes from sepsis patients compared to healthy controls. These elevated exosomal mtDNA levels correlated with disease severity and showed a positive association with lung injury markers, including SRAGE, SP-D, and CC16. In vitro experiments demonstrated that both isolated mtDNA and exosomes significantly impaired mitochondrial membrane potential, increased reactive oxygen species (ROS) levels, and reduced the oxygen consumption rate (OCR), suggesting the induction of mitochondrial dysfunction. Moreover, mtDNA promoted endothelial cell damage and increased permeability via PKCδ. Crucially, PKCδ knockdown markedly restored mtDNA-induced mitochondrial dysfunction and cellular permeability damage. In conclusion, Exosome-derived mtDNA triggers mitochondrial dysfunction and endothelial barrier disruption via PKCδ, promoting sepsis progression, suggesting potential therapeutic targets.