Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Mol Neurobiol. 2022 Dec;59(12):7075-7094. doi: 10.1007/s12035-022-03008-w. Epub 2022 Sep 9.
Excessive alcohol consumption can lead to alterations in brain structure and function, even causing irreversible learning and memory disorders. The hippocampus is one of the most sensitive areas to alcohol neurotoxicity in the brain. Accumulating evidence indicates that mitochondrial dysfunction contributes to alcohol neurotoxicity. However, little is known about the underlying molecular mechanisms. In this study, we found that chronic exposure to ethanol caused abnormal mitochondrial fission/fusion and morphology by activating the mitochondrial fission protein dynamin-related protein 1 (Drp1) and upregulating Drp1 receptors, such as fission protein 1 (Fis1), mitochondrial dynamics protein of 49 kDa (Mid49), and mitochondrial fission factor (Mff), combined with decreasing optic atrophy 1 (Opa1) and mitochondrial fusion protein mitofusin 1 (Mfn1) levels. In addition, mitochondrial division inhibitor 1 (mdivi-1) abrogated ethanol-induced mitochondrial dysfunction and improved hippocampal synapses and cognitive function in ethanol-exposed mice. Chronic ethanol exposure also resulted in cyclin-dependent kinase 5 (Cdk5) overactivation, as shown by the increase in the levels of Cdk5 and its activator P25 in the hippocampus. Furthermore, a Cdk5/P25 inhibitor (roscovitine) or Cdk5 knockdown using small interfering RNA (LVi-Cdk5) exerted neuroprotection by inhibiting abnormal mitochondrial fission through Drp1 phosphorylation at Ser616 and mitochondrial translocation after chronic ethanol exposure. Taken together, the present study demonstrated that inhibition of aberrant Cdk5 activation attenuates hippocampal neuron injury and cognitive deficits induced by chronic exposure to ethanol through Drp1-mediated mitochondrial fission and mitochondrial dysfunction. Interfering with this pathway might serve as a potential therapeutic approach to prevent ethanol-induced neurotoxicity in the brain.
过量饮酒会导致大脑结构和功能发生改变，甚至引起不可逆转的学习和记忆障碍。海马体是大脑中对酒精神经毒性最敏感的区域之一。越来越多的证据表明，线粒体功能障碍与酒精神经毒性有关。然而，关于其潜在的分子机制知之甚少。在这项研究中，我们发现慢性乙醇暴露通过激活线粒体裂变蛋白 dynamin-related protein 1（Drp1）并上调 Drp1 受体，如裂变蛋白 1（Fis1）、线粒体动力学蛋白 49 kDa（Mid49）和线粒体裂变因子（Mff），导致异常的线粒体裂变/融合和形态，同时降低视神经萎缩 1（Opa1）和线粒体融合蛋白 mitofusin 1（Mfn1）的水平，从而导致异常的线粒体裂变/融合和形态。此外，线粒体分裂抑制剂 1（mdivi-1）可阻断乙醇诱导的线粒体功能障碍，并改善乙醇暴露小鼠的海马突触和认知功能。慢性乙醇暴露还导致周期蛋白依赖性激酶 5（Cdk5）过度激活，表现为海马体中 Cdk5 及其激活剂 P25 水平的增加。此外，使用 Cdk5/P25 抑制剂（roscovitine）或小干扰 RNA（LVi-Cdk5）敲低 Cdk5 可通过抑制 Cdk5 磷酸化 Drp1 第 616 位丝氨酸和慢性乙醇暴露后的线粒体易位来发挥神经保护作用，从而抑制异常的线粒体裂变。总之，本研究表明，抑制异常的 Cdk5 激活可通过 Drp1 介导的线粒体裂变和线粒体功能障碍来减轻慢性乙醇暴露引起的海马神经元损伤和认知缺陷。干扰这条通路可能成为预防大脑中乙醇诱导的神经毒性的一种潜在治疗方法。
