线粒体自噬选择性地消除受损或功能失调的线粒体,在维持线粒体质量控制中起着至关重要的作用。然而,目前尚不清楚线粒体自噬是否可以完全激活,以及在SCI后如何演变.我们对来自假手术和SCI后1、3、5和7天的动物样品的RNA-seq分析表明,在急性和亚急性早期阶段确实抑制了线粒体自噬。体外实验表明,这种抑制作用与活性氧(ROS)的过量产生和BNIP3的下调密切相关。过量的ROS导致线粒体自噬通量的阻断,伴有进一步的线粒体功能障碍和神经元凋亡增加。幸运的是,研究发现,通过BNIP3-LC3的相互作用,有逆转氧化应激诱导的BNIP3下调并增强线粒体自噬的能力,减轻线粒体功能障碍并最终减少神经元凋亡。进一步的动物实验表明,LIG减轻氧化应激和线粒体自噬抑制,拯救神经元凋亡,促进组织修复,最终导致改善运动功能。总之,这项研究阐明了SCI后线粒体自噬抑制的状态及其潜在机制,并证实了LIG通过BNIP3-LC3增强线粒体自噬的作用,为修复SCI提供了新的治疗靶点和策略。
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.