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This work aims to evaluate the protective effects of Mdivi-1, a Drp1 inhibitor, on sepsis-induced acute lung injury and explore underlying mechanisms.

May 16, 2026Open Access

Inhibition of Drp1 improves mitochondrial dynamics imbalance and alleviates sepsis-induced acute lung injury

Key Points

This work aims to evaluate the protective effects of Mdivi-1, a Drp1 inhibitor, on sepsis-induced acute lung injury and explore underlying mechanisms.
In vivo sepsis-induced acute lung injury was induced using cecal ligation and puncture in mice.
In vitro models were created with MLE-12 cells exposed to lipopolysaccharide to assess injury response.
Assessment included histological staining, cytokine measurements, Western blot analysis, and apoptosis assays.
Mdivi-1 treatment significantly reduced lung injury and inflammation, restoring Occludin and ZO-1 expression.
Treatment led to decreased ROS levels, improved mitochondrial membrane potential, and enhanced ATP production.
Inhibition of the CaN/Drp1 pathway was observed, indicating a key protective mechanism.

Abstract

Acute lung injury (ALI) is a major complication of sepsis. Sepsis-induced ALI (S-ALI) is closely related to excessive mitochondrial fission induced by the fission protein dynamin-related protein 1 (Drp1), and this process may be modulated in part through the calcineurin (CaN)/Drp1 signaling pathway. This work aimed to assess the protective impact of Mdivi-1, a Drp1 inhibitor, on ALI caused by sepsis and to clarify the associated molecular mechanisms. In vivo experiments employed the cecal ligation and puncture (CLP) method to induce sepsis-associated ALI in mice. In vitro, an MLE-12 mouse alveolar epithelial cell model was induced by lipopolysaccharide (LPS). Lung injury and inflammation were evaluated through histological staining, lung wet-to-dry ratio, and measurement of inflammatory cytokines; Western blot was used to assess proteins related to mitochondrial dynamics, the CaN/Drp1 signaling pathway, and apoptosis; cell apoptosis was analyzed using fluorescence-based assays, and reactive oxygen species (ROS) accumulation as well as mitochondrial membrane potential (ΔΨm) changes were measured. CLP-induced mice and LPS-treated MLE-12 cells exhibited significant lung injury, elevated inflammatory cytokines, decreased mitochondrial fusion proteins, increased fission proteins, elevated ROS levels, reduced ΔΨm, decreased ATP production, and increased apoptosis. Mdivi-1 treatment markedly alleviated CLP/LPS-induced lung injury and inflammation, restored the expression of Occludin and zonula occludens-1 (ZO-1), improved abnormal mitochondrial dynamics, reduced ROS levels, restored ΔΨm and adenosine triphosphate (ATP) content, and inhibited apoptosis. In addition, Mdivi-1 blocked dysregulated activation of the CaN/Drp1 signaling pathway. The Drp1 inhibitor Mdivi-1 alleviates S-ALI by inhibiting the CaN/Drp1 signaling pathway, improving mitochondrial dynamics imbalance, reducing oxidative stress and apoptosis, and partially restoring the alveolar epithelial barrier. The present findings imply that interventions aimed at Drp1 and mitochondrial dynamics regulation might serve as a viable therapeutic option for S-ALI.

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