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

Summary

This mechanistic study identifies mitoFLARE, a mitochondrial nanotube system that supports inner membrane exchange under early inflammatory stress. As inflammation advances, loss of MICOS-SAM anchoring suppresses mitoFLARE, promotes mtDNA cytosolic release, and activates cGAS-STING, driving immune dysregulation and organ injury.

Key Findings

• Early LPS induces mitochondria to form flagella-like extensions (mitoFLARE) via glycosylated TRAK1–FHL2–actin assembly, shifting from fusion to nanotube-mediated transport.
• Progressive inflammation disrupts MICOS-SAM anchoring, suppresses mitoFLARE, and enhances ER–mitochondria contacts leading to outer membrane rupture.
• mtDNA release activates cGAS-STING signaling, triggering immune dysregulation, inflammatory storm, programmed cell death, and organ dysfunction.

Clinical Implications

Targeting preservation of mitoFLARE dynamics or modulating cGAS-STING signaling could mitigate immune dysregulation and organ failure in sepsis.

Limitations

• Preclinical LPS-based models may not capture full human sepsis heterogeneity
• Lack of interventional in vivo validation targeting mitoFLARE or cGAS-STING within sepsis models

Future Directions

Validate mitoFLARE dynamics and cGAS-STING dependence in human tissues and septic models; develop pharmacologic or genetic strategies to preserve mitoFLARE or modulate STING.