Enhancing mitophagy by ligustilide through BNIP3-LC3 interaction attenuates oxidative stress-induced neuronal apoptosis in spinal cord injury

TL;DR

This study shows that ligustilide enhances mitophagy to reduce neuronal death and improve recovery after spinal cord injury.

Contribution

The study reveals that ligustilide reverses mitophagy inhibition via BNIP3-LC3 interaction in spinal cord injury.

Findings

Mitophagy is inhibited in the early stages of spinal cord injury due to oxidative stress and BNIP3 downregulation.

Ligustilide reverses oxidative stress and restores mitophagy, reducing neuronal apoptosis and improving motor function.

Ligustilide promotes tissue repair and functional recovery in spinal cord injury animal models.

Abstract

Mitophagy selectively eliminates damaged or dysfunctional mitochondria, playing a crucial role in maintaining mitochondrial quality control. However, it remains unclear whether mitophagy can be fully activated and how it evolves after SCI. Our RNA-seq analysis of animal samples from sham and 1, 3, 5, and 7 days post-SCI indicated that mitophagy was indeed inhibited during the acute and subacute early stages. In vitro experiments showed that this inhibition was closely related to excessive production of reactive oxygen species (ROS) and the downregulation of BNIP3. Excessive ROS led to the blockage of mitophagy flux, accompanied by further mitochondrial dysfunction and increased neuronal apoptosis. Fortunately, ligustilide (LIG) was found to have the ability to reverse the oxidative stress-induced downregulation of BNIP3 and enhance mitophagy through BNIP3-LC3 interaction, alleviating mitochondrial dysfunction and ultimately reducing neuronal apoptosis. Further animal experiments demonstrated that LIG alleviated oxidative stress and mitophagy inhibition, rescued neuronal apoptosis, and promoted tissue repair, ultimately leading to improved motor function. In summary, this study elucidated the state of mitophagy inhibition following SCI and its potential mechanisms, and confirmed the effects of LIG-enhanced mitophagy through BNIP3-LC3, providing new therapeutic targets and strategies for repairing SCI.

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