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Endoplasmic Reticulum Stress Inhibition Promotes Mitophagy via Miro1 Reduction to Rescue Mitochondrial Dysfunction

Yuqi Wen1, Zheng Han1,2, Bao Wang1,3

  • 1Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi'an, 710038, Shaanxi, China.

Cellular and Molecular Neurobiology
|May 29, 2025
PubMed

Insights

Endoplasmic reticulum stress (ERS) contributes to Parkinson's disease (PD) pathogenesis by impairing mitochondria. Suppressing ERS with 4-phenylbutyric acid (4-PBA) protects neurons and improves motor function in PD models.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Mitochondrial dysfunction and endoplasmic reticulum stress (ERS) are implicated in Parkinson's disease (PD) pathogenesis.
  • The precise regulatory mechanisms linking ERS and mitochondrial dysfunction in PD remain elusive.

Purpose of the Study:

  • To investigate the relationship between ERS and mitochondrial dysfunction in a Parkinson's disease model.
  • To evaluate the therapeutic potential of targeting ERS in PD.

Main Methods:

  • Utilized an in vitro Parkinson's disease model induced by methyl-4-phenylpyridine (MPP+).
  • Assessed ERS using ER staining and immunofluorescence for ERS-related proteins.
  • Examined ER morphology via transmission electron microscopy (TEM).
  • Investigated the effects of 4-phenylbutyric acid (4-PBA) on apoptosis, ER morphology, mitochondrial function, and the Miro1-mitophagy axis.
  • Conducted in vivo experiments in PD models.

Main Results:

  • MPP+-induced PD models exhibited increased intracellular peroxidation and significant ERS with ER depletion.
  • 4-PBA treatment suppressed ERS, reduced apoptosis, and restored ER micromorphology.
  • 4-PBA alleviated mitochondrial dysfunction, evidenced by increased mitochondrial membrane potential (MMP), upregulated electron transport chain proteins, and restored mitochondrial integrity.
  • The therapeutic effects of 4-PBA were linked to modulation of the Miro1-mitophagy axis.
  • Inhibition of ERS in vivo reduced dopaminergic neuron loss and improved cognitive and motor functions.

Conclusions:

  • ERS plays a critical role in the pathogenesis of Parkinson's disease.
  • Targeting ERS, for example, with 4-PBA, offers a promising therapeutic strategy for PD by mitigating mitochondrial dysfunction and neurodegeneration.
Keywords:
Endoplasmic reticulum stressMiro1MitophagyParkinson’s disease

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