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

Sepsis-induced cardiac dysfunction arises from complex intercellular communication networks that extend beyond direct cardiomyocyte damage, yet the nanoscale mechanisms governing these interactions remain poorly understood. Here, we identify tunneling nanotubes (TNTs) as dynamic biological nanostructures facilitating intercellular mitochondrial transfer, revealing their critical role in septic cardiac remodeling. Using a murine cecal ligation and puncture (CLP) model and single-cell RNA sequencing, we demonstrate that sepsis reprograms cardiac endothelial cells, fibroblasts, and macrophages, generating metabolically impaired subpopulations with dysfunctional mitochondrial respiration. We uncover a Drp1-driven cytoskeletal remodeling process that orchestrates TNT biogenesis, wherein Drp1 interacts with Filamin and Kinesin to regulate TNT formation and extension, enabling long-range organelle trafficking. Cardiac-specific Drp1 knockout disrupts TNT-mediated mitochondrial exchange, halting metabolic deterioration and reversing cellular reprogramming. These findings establish Drp1-mediated TNT networks as nanoscale conduits of organelle communication, offering insights into biological nanotube engineering, cellular-scale nanotechnology, and potential therapeutic interventions for mitochondrial dysfunction in sepsis.