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Background <p>Neurodegeneration is a chronic, progressive process initiated by early neurite retraction, a pathological hallmark preceding neuronal death in neurodegenerative disorders such as Parkinson’s disease (PD). Cleavage of gasdermin E (GSDME) releases its N-terminal domain (GSDME-N), which has been shown to mediate mitochondrial dysfunction and the onset of neurodegeneration. However, the therapeutic potential of targeting GSDME-N for early intervention in PD, and whether nicotine, a tobacco component with neuroprotective properties, acts through GSDME modulation remain unexplored.</p> Methods <p>The SH-SY5Y cells, primary neurons and C57BL mice were treated with rotenone to model neurodegeneration in PD. Mitochondrial accumulation of GSDME-N and activation of autophagy were assessed via immunoblotting and immunostaining. Mitochondrial membrane potential was evaluated using JC-1 and TMRM fluorescent dyes, while mitochondrial reactive oxygen species were detected with MitoSOX™ Red superoxide indicator. For morphological analysis, immunofluorescence staining was performed using antibodies against microtubule-associated protein 2 (MAP2) to visualize neurites, along with MitoTracker to label mitochondria within neurites. In vivo, C57BL/6 mice were administered rotenone and provided with nicotine supplementation in their drinking water. Motor function was assessed using rotarod, hanging wire and pole tests. Tyrosine hydroxylase (TH)-positive neurons and fibers were detected using immunohistochemistry.</p> Results <p>We demonstrated that GSDME-N accumulation on mitochondria during early neurodegeneration was suppressed by nicotine, thereby maintaining mitochondrial homeostasis and preventing neurite retraction. Mechanistically, nicotine activated autophagic pathway to promote GSDME-N clearance, which maintained mitochondrial membrane potential, reduced reactive oxygen species (ROS) production, and specifically rescued mitochondrial function. This protective mechanism significantly attenuated early pathological changes, including neurite retraction and loss. In a rotenone-induced PD model, nicotine treatment effectively reduced GSDME-N accumulation and decelerated neurodegenerative progression.</p> Conclusions <p>These findings reveal the critical role of GSDME-N in early-stage mitochondrial damage in PD and propose a novel therapeutic strategy targeting the nicotine-autophagy axis to counteract GSDME-N-mediated neurodegeneration.</p>

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GSDME-N-induced mitochondrial neurotoxicity in early neurodegeneration was suppressed by nicotine via enhancing autophagic flux

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月31日

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  • Junjun Zhao,
  • Saitao Qiu,
  • Angyang Guo,
  • Haixia Huang,
  • Wei Wang,
  • Jianliang Zhang

摘要

Background

Neurodegeneration is a chronic, progressive process initiated by early neurite retraction, a pathological hallmark preceding neuronal death in neurodegenerative disorders such as Parkinson’s disease (PD). Cleavage of gasdermin E (GSDME) releases its N-terminal domain (GSDME-N), which has been shown to mediate mitochondrial dysfunction and the onset of neurodegeneration. However, the therapeutic potential of targeting GSDME-N for early intervention in PD, and whether nicotine, a tobacco component with neuroprotective properties, acts through GSDME modulation remain unexplored.

Methods

The SH-SY5Y cells, primary neurons and C57BL mice were treated with rotenone to model neurodegeneration in PD. Mitochondrial accumulation of GSDME-N and activation of autophagy were assessed via immunoblotting and immunostaining. Mitochondrial membrane potential was evaluated using JC-1 and TMRM fluorescent dyes, while mitochondrial reactive oxygen species were detected with MitoSOX™ Red superoxide indicator. For morphological analysis, immunofluorescence staining was performed using antibodies against microtubule-associated protein 2 (MAP2) to visualize neurites, along with MitoTracker to label mitochondria within neurites. In vivo, C57BL/6 mice were administered rotenone and provided with nicotine supplementation in their drinking water. Motor function was assessed using rotarod, hanging wire and pole tests. Tyrosine hydroxylase (TH)-positive neurons and fibers were detected using immunohistochemistry.

Results

We demonstrated that GSDME-N accumulation on mitochondria during early neurodegeneration was suppressed by nicotine, thereby maintaining mitochondrial homeostasis and preventing neurite retraction. Mechanistically, nicotine activated autophagic pathway to promote GSDME-N clearance, which maintained mitochondrial membrane potential, reduced reactive oxygen species (ROS) production, and specifically rescued mitochondrial function. This protective mechanism significantly attenuated early pathological changes, including neurite retraction and loss. In a rotenone-induced PD model, nicotine treatment effectively reduced GSDME-N accumulation and decelerated neurodegenerative progression.

Conclusions

These findings reveal the critical role of GSDME-N in early-stage mitochondrial damage in PD and propose a novel therapeutic strategy targeting the nicotine-autophagy axis to counteract GSDME-N-mediated neurodegeneration.