Mitochondrial flagella-like extensions (MitoFLARE) dysfunction triggers STING-mediated immune dysregulation in sepsis.

Sepsis is an immune dysregulation syndrome triggered by infection, characterized by host self-damage due to immune imbalances. This study focuses on dynamic changes of mitochondrial symbiotic function in host cells during sepsis and systematically investigates dysregulation of mitochondrial communication modes and the intrinsic link between mitochondrial DNA (mtDNA) release and immune dysregulation. We demonstrate that during early-stage LPS treatment, mitochondria actively remodel by extruding flagella-like extensions (termed mitoFLARE). These structures, nanotubes mediating long-distance transport, form through glycosylated TRAK1 binding FHL2 to drive actin network formation, thereby shifting mitochondrial communication from direct fusion to nanotube-mediated transport. This helps maintain dynamic exchange within the inner mitochondrial membrane under LPS treatment. However, as inflammation progresses, deteriorated mitochondrial quality control disrupts the MICOS-SAM complex, abrogates inner-outer membrane anchoring, and suppresses mitoFLARE functions. All these ultimately enhance endoplasmic reticulum-mitochondrial contacts to promote outer membrane rupture and result in mtDNA release into the cytoplasm to activate cGAS-STING signaling, further triggering immune dysregulation and inflammatory storm, culminating in programmed cell death and organ dysfunction. This study elucidates the pivotal role of dysregulated mitochondrial-host symbiosis in sepsis progression and provides important insights into the underlying mechanisms of sepsis-associated immune imbalances, laying a theoretical foundation for targeted therapy development.