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

Summary

This mechanistic study identifies mitochondrial flagella-like extensions (MitoFLARE) as a dynamic communication mode that preserves mitochondrial function early in endotoxin exposure, and shows that failure of this system promotes ER-mitochondria contacts, mtDNA cytosolic release, and cGAS-STING activation during sepsis. The work links mitochondrial structural remodeling to innate immune dysregulation, offering new therapeutic targets upstream of STING.

Key Findings

• Early LPS exposure induces mitochondrial MitoFLARE nanotubes via glycosylated TRAK1–FHL2–actin assembly, shifting communication from fusion to nanotube-mediated transport.
• Progressive inflammation disrupts the MICOS–SAM complex, increases ER–mitochondria contacts, and suppresses MitoFLARE, leading to outer membrane rupture and mtDNA release.
• Cytosolic mtDNA activates cGAS–STING signaling, driving immune dysregulation, inflammatory storm, and programmed cell death during sepsis.

Clinical Implications

Although preclinical, targeting the mitoFLARE machinery or stabilizing MICOS–SAM and ER–mitochondria interfaces could dampen cGAS–STING activation and mitigate organ injury in sepsis. It suggests biomarkers (mtDNA, ER–mitochondria contact signatures) for patient stratification in trials.

Limitations

• Predominantly LPS-based models; generalizability to diverse human sepsis etiologies remains to be validated
• Translational biomarkers and druggable nodes require in vivo therapeutic testing

Future Directions

Validate MitoFLARE and MICOS–SAM stabilization strategies in polymicrobial sepsis and clinically relevant models; develop inhibitors/modulators of TRAK1–FHL2 interactions; evaluate mtDNA and ER–mitochondria contact biomarkers in ICU cohorts.