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Squamosamide Derivative FLZ Diminishes Aberrant Mitochondrial Fission by Inhibiting Dynamin-Related Protein 1

Hanyu Yang1, Lu Wang1, Caixia Zang1

  • 1State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Frontiers in Pharmacology
|April 5, 2021
PubMed

Insights

FLZ protects against Parkinson's disease by inhibiting Drp1-mediated mitochondrial fission. This treatment restores mitochondrial function and protects dopaminergic neurons in both cell cultures and mouse models.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Mitochondrial Biology

Background:

  • Mitochondrial dysfunction and fragmentation are implicated in Parkinson's disease (PD) pathogenesis.
  • Dynamin-related protein 1 (Drp1) controls mitochondrial fission, and its dysregulation contributes to neurodegeneration.
  • The therapeutic potential of FLZ in PD, particularly its effect on mitochondrial dynamics, remains largely uncharacterized.

Purpose of the Study:

  • To investigate the effect of FLZ on mitochondrial dynamics and its role in neuroprotection against 1-methyl-4-phenylpyridinium (MPP+)-induced damage in neurons.
  • To validate the findings in an MPTP-induced Parkinson's disease mouse model.

Main Methods:

  • In vitro studies using cultured neurons exposed to MPP+
  • Assessing the impact of FLZ on Drp1 activity, mitochondrial fission, reactive oxygen species (ROS) production, mitochondrial integrity, and synaptic plasticity.
  • In vivo studies using an MPTP-induced PD mouse model to evaluate Drp1 translocation, mitochondrial fragmentation, dopaminergic neuron survival, dopamine levels, and motor function.

Main Results:

  • FLZ inhibited Drp1 activity and reduced excessive mitochondrial fission in MPP+-treated neurons.
  • FLZ preserved mitochondrial integrity, reduced ROS production, and protected dopaminergic neurons by restoring mitochondrial distribution and synaptic branches.
  • In vivo, FLZ decreased Drp1 translocation and mitochondrial fragmentation in the substantia nigra of PD mice, protected dopaminergic neurons, and improved motor coordination.

Conclusions:

  • FLZ exerts neuroprotection in Parkinson's disease models by inhibiting Drp1-mediated mitochondrial fission.
  • FLZ treatment improves mitochondrial function, reduces oxidative stress, and preserves dopaminergic neuron integrity.
  • FLZ demonstrates therapeutic potential for Parkinson's disease through a novel mechanism involving the regulation of mitochondrial dynamics.
Keywords:
DRP1FLZParkinson’s diseasemitochondrial dyanmicsmpp+

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