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

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

  • Sci Adv. 2026 Mar 13;12(11):eadz3266. doi: 10.1126/sciadv.adz3266.
Rui Song 1,  Cheng Huang 1 2,  Yinrui Ma 1,  Zhenhua Zhang 1 3,  Yifei Liu 1 4,  Bing Chen 1,  Xi Zhang 1,  Shuai Hao 5,  He Huang 1,  Milad Ashrafizadeh 6,  João Conde 1 7,  Chenyang Duan 1
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine and Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China.
  • 2 The First Affiliated Hospital of Hunan University of Medicine, Huihua 418000, P.R. China.
  • 3 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China.
  • 4 The First College of Clinical Medical Science, China Three Gorges University, Yichang 443008, P.R. China.
  • 5 Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, P.R. China.
  • 6 Department of Radiation Oncology, Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan 250000, P.R. China.
  • 7 Comprehensive Health Research Centre (CHRC), NOVA Medical School, Faculdade de Ciências Médicas, NMS
  • 8
PMID: 41811940 DOI: 10.1126/sciadv.adz3266
Abstract

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.

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