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Disulfidptosis contributes to rotenone-induced dopaminergic neuron damage

Wenqi Ye1, Qifu Zhang, Wei Ge

  • 1Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, China.

Neural Regeneration Research
|October 31, 2025
PubMed
Abstract

No abstract available in PubMed .

Insights

Rotenone exposure triggers cystine accumulation and abnormal disulfide bonds, leading to disulfidptosis (cell death) in dopaminergic neurons, offering new insights into Parkinson's disease pathogenesis.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Parkinson's disease (PD) pathogenesis is not fully understood.
  • Rotenone exposure is linked to PD.
  • Disulfidptosis is a newly identified cell death pathway implicated in PD.

Purpose of the Study:

  • Investigate the role of disulfidptosis in rotenone-induced dopaminergic neurodegeneration.
  • Elucidate the molecular mechanisms underlying rotenone-induced cell death.

Main Methods:

  • Proteomic analysis of rotenone-exposed dopaminergic neurons.
  • Gene Expression Omnibus (GEO) database analysis for PD-associated genes.
  • Assessment of disulfide bond formation and protein expression.

Main Results:

  • Proteomics identified altered disulfidptosis-related proteins in rotenone-exposed neurons.
  • Increased abnormal disulfide bond formation and cystine accumulation were observed.
  • Upregulation of solute carrier family 7 member 11 (SLC7A11) and SLC3A2 correlated with extracellular matrix protein 1 (ECM1).
  • The Ras-related C3 botulinum toxin substrate 1 (RAC1)/WAVE regulatory complex/actin-related protein 2/3 (ARP2/3) pathway activation led to cytoskeleton collapse.

Conclusions:

  • Rotenone induces cystine accumulation via SLC7A11 upregulation, potentially mediated by ECM1, leading to disulfidptosis.
  • Disulfidptosis in this model is characterized by cytoskeleton collapse.
  • Findings provide novel perspectives on neurodegenerative disease mechanisms and potential therapeutic targets.
Keywords:
Parkinson’s diseaseSLC7A11cell deathcystinecytoskeletondisulfidptosisdopaminergic neuronneurodegenerationoxidative stressrotenone

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