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

TL;DR

The paper shows how cytoskeletal changes in heart cells during sepsis lead to the formation of nanotubes that transfer mitochondria, offering new insights into cardiac dysfunction and potential treatments.

Contribution

The study reveals Drp1-driven cytoskeletal remodeling as a novel mechanism for tunneling nanotube formation and mitochondrial transfer in septic cardiac cells.

Findings

Sepsis reprograms cardiac endothelial cells, fibroblasts, and macrophages, leading to mitochondrial dysfunction.

Drp1 interacts with Filamin and Kinesin to regulate tunneling nanotube formation and mitochondrial transfer.

Cardiac-specific Drp1 knockout halts metabolic deterioration and reverses cellular reprogramming in sepsis.

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.

Cytoskeletal remodeling by Drp1 promotes nanotube formation and mitochondrial transfer in septic hearts.

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