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

Summary

Using CLP sepsis and single-cell RNA-seq, the study shows that Drp1-driven cytoskeletal remodeling orchestrates TNT biogenesis that mediates mitochondrial transfer among cardiac resident cells. Cardiac Drp1 knockout disrupts TNT-mediated exchange, reversing metabolic deterioration and cellular reprogramming during sepsis.

Key Findings

• Single-cell RNA-seq in CLP sepsis revealed metabolically impaired subpopulations among endothelial cells, fibroblasts, and macrophages with dysfunctional mitochondrial respiration.
• Drp1 interacts with Filamin and Kinesin to coordinate TNT biogenesis and extension, enabling long-range mitochondrial trafficking.
• Cardiac-specific Drp1 knockout abrogated TNT-mediated mitochondrial exchange, halted metabolic deterioration, and reversed cellular reprogramming in sepsis.

Clinical Implications

Targeting Drp1 or TNT biogenesis could become a strategy to prevent or reverse septic cardiomyopathy. Translation will require pharmacologic modulation studies, safety profiling, and human tissue validation.

Limitations

• Findings are limited to murine models; no human myocardial validation presented.
• Lack of pharmacologic modulation data to complement genetic knockout and address translatability and safety.

Future Directions

Evaluate pharmacologic Drp1/TNT modulators, validate TNT-mediated mitochondrial transfer in human cardiac tissues, and develop imaging biomarkers to monitor TNT networks in vivo.