Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong, PR China; Collaborative Innovation Platform for Modernization and Industrialization of Regional Characteristic Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong, PR China.
Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong, PR China.
Neuropharmacology. 2022 Aug 15;214:109154. doi: 10.1016/j.neuropharm.2022.109154. Epub 2022 Jun 1.
Neuronal dendrites and dendritic spines are essential for normal synaptic transmission and may be critically involved in the pathophysiology of various neurological disorders, including depression. Emerging data supports the role of mitochondria in dendritic protrusions in modulating the development and morphological plasticity of spines. Mitophagy, a mitochondria-specific form of autophagy, is the fundamental process of clearing damaged mitochondria to maintain cellular homeostasis. As a brain-specific microRNA, miR-134 is localized to the synaptodendritic compartment of hippocampal neurons and negatively regulates the development of dendritic spines. However, the role of miR-134 in mitophagy related to dendritic deficits in the pathophysiology of depression remains unclear. In this study, we showed that miR-134-5p knockdown abrogated depression-like behavioral symptoms and corrected aberrant spine morphology in hippocampal neurons of chronic unpredictable mild stress (CUMS) mice. Moreover, knockdown of miR-134-5p triggered autophagy in dendrites, improved mitochondrial impairment, and induced the generation of autophagosomes in the hippocampus of CUMS mice. We further found that AMP-activated protein kinase (AMPK), which mediates the impairment of defective mitochondria via mitophagy, can bind directly to miR-134-5p and is negatively regulated by this miRNA. This study demonstrates that miR-134-5p exerts an enormous effect on dendritic deficits by promoting AMPK-mediated mitophagy and provides a potential new target for antidepressant drug research and development.
神经元树突和树突棘对于正常的突触传递至关重要，并且可能在各种神经障碍的病理生理学中起关键作用，包括抑郁症。新出现的数据支持线粒体在树突状突起中调节棘突的发育和形态可塑性的作用。线粒体自噬是一种清除受损线粒体以维持细胞内稳态的基本过程。作为一种脑特异性 microRNA，miR-134 定位于海马神经元的突触树突区，负调控树突棘的发育。然而，miR-134 在与抑郁症病理生理学中树突状缺陷相关的线粒体自噬中的作用尚不清楚。在这项研究中，我们表明 miR-134-5p 的敲低消除了慢性不可预测轻度应激 (CUMS) 小鼠的抑郁样行为症状，并纠正了海马神经元中异常的棘突形态。此外，miR-134-5p 的敲低在 CUMS 小鼠的树突中触发了自噬，改善了线粒体损伤，并诱导了自噬体的生成。我们进一步发现，通过线粒体自噬介导受损线粒体损伤的 AMP 激活蛋白激酶 (AMPK) 可以直接与 miR-134-5p 结合，并受该 miRNA 的负调控。这项研究表明，miR-134-5p 通过促进 AMPK 介导的线粒体自噬对树突状缺陷产生巨大影响，为抗抑郁药的研究和开发提供了一个潜在的新靶点。
