Cytoskeletal remodeling promotes tunneling nanotube formation and drives cardiac resident cell mitochondrial transfer in sepsis.

Summary

Using a CLP sepsis model and single-cell RNA-seq, the authors show that Drp1-driven cytoskeletal remodeling orchestrates tunneling nanotube biogenesis in cardiac cells, enabling long-range mitochondrial trafficking. Drp1’s interaction with Filamin and Kinesin regulates TNT formation/extension, and cardiac-specific Drp1 knockout disrupts mitochondrial exchange, halting metabolic deterioration and reversing cellular reprogramming.

Key Findings

• Sepsis reprogrammed cardiac endothelial cells, fibroblasts, and macrophages into metabolically impaired subpopulations with dysfunctional mitochondrial respiration.
• Drp1-driven cytoskeletal remodeling, via interactions with Filamin and Kinesin, orchestrated TNT biogenesis and extension for organelle trafficking.
• Cardiac-specific Drp1 knockout disrupted TNT-mediated mitochondrial exchange, halting metabolic deterioration and reversing cellular reprogramming.

Clinical Implications

While preclinical, targeting Drp1/TNT-mediated mitochondrial exchange could represent a novel strategy to prevent or reverse septic cardiomyopathy; translation will require validation in human tissues and pharmacologic modulation studies.

Limitations

• Preclinical mouse model without human tissue validation limits direct translational generalizability.
• Lack of survival or organ-level functional outcomes beyond cellular/metabolic endpoints.

Future Directions

Validate TNT-mediated mitochondrial transfer and Drp1 dependency in human septic myocardium; test pharmacologic Drp1 modulators; map TNT networks across cell types and disease stages; quantify organ-level functional rescue.