Endoplasmic Reticulum Stress Inhibition Promotes Mitophagy via Miro1 Reduction to Rescue Mitochondrial Dysfunction and Protect Dopamine Neurons in Parkinson's Disease.

Abstract

Both mitochondrial dysfunction and endoplasmic reticulum stress (ERS) have been implicated in the pathogenesis of Parkinson's disease (PD). However, the underlying regulatory mechanisms between ERS and mitochondrial dysfunction remain unclear. In the present study, we found that an in vitro model of Parkinson's disease (PD) induced by methyl-4-phenylpyridine (MPP⁺) showed increased intracellular peroxidation, leading to a significant increase in ERS. ER staining and immunofluorescence analysis of ERS-related proteins verified the presence of ERS, whereas transmission electron microscopy (TEM) showed complete depletion of ER. Notably, treatment with 4-phenylbutyric acid (4-PBA) to suppress ERS reduced apoptosis and concurrently reversed the ER micromorphology. Furthermore, 4-PBA alleviated mitochondrial dysfunction, as shown by increased mitochondrial membrane potential (MMP), upregulation of electron transport chain proteins, and restoration of mitochondrial integrity. Further studies revealed that the effect of 4-PBA could be attributed to the modulation of the mitochondrial Rho-GTPase 1 (Miro1)-mitophagy axis. In vivo experiments in Parkinson's disease models demonstrated that inhibiting ERS reduced dopaminergic neuron loss while improving cognitive and motor function. Collectively, these findings indicate that treatments targeting ERS may be potential candidates for treating PD.