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

Summary

This mechanistic study identifies Drp1-driven cytoskeletal remodeling as the trigger for tunneling nanotube biogenesis, enabling long-range mitochondrial transfer among cardiac resident cells in sepsis. Cardiac-specific Drp1 knockout disrupted TNT-mediated exchange, prevented metabolic deterioration, and reversed cellular reprogramming, implicating TNT networks as actionable targets in septic cardiomyopathy.

Key Findings

• Tunneling nanotubes (TNTs) facilitate intercellular mitochondrial transfer in septic hearts, identified using a murine CLP model and single-cell RNA sequencing.
• Drp1-driven cytoskeletal remodeling, via interactions with Filamin and Kinesin, orchestrates TNT biogenesis and extension for long-range organelle trafficking.
• Cardiac-specific Drp1 knockout disrupts TNT-mediated mitochondrial exchange, halts metabolic deterioration, and reverses sepsis-induced cellular reprogramming.

Clinical Implications

Although preclinical, targeting Drp1-dependent TNT formation or stabilizing mitochondrial quality control could mitigate septic cardiac dysfunction. This supports biomarker development for mitochondrial distress and motivates testing TNT/Drp1 modulators in large-animal and early-phase clinical studies.

Limitations

• Preclinical murine data without human tissue or clinical validation
• Potential pleiotropic effects of Drp1 manipulation beyond TNT biology

Future Directions

Validate TNT prevalence and Drp1 pathway activity in human septic myocardium, develop small-molecule or biologic TNT/Drp1 modulators, and test myocardial energetic/function endpoints in large-animal sepsis models.