Microcystin-leucine-arginine induced neurotoxicity by initiating mitochondrial fission in hippocampal neurons
Microcystin-leucine-arginine induced neurotoxicity by initiating mitochondrial fission in hippocampal neurons
复制标题
微囊藻毒素-亮氨酸-精氨酸通过启动海马神经元线粒体裂变诱导神经毒性
DOI：
10.1016/j.scitotenv.2019.134702
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发表时间：
2020
影响因子：
9.8
通讯作者：
Xiaodong Han
中科院分区：
文献类型：
--
作者：
Changliang Zhang;Jing Wang;Jinling Zhu;Yabing Chen;Xiaodong Han
微囊藻毒素-亮氨酸-精氨酸（MC-LR）可以穿过血脑屏障（BBB）并表现出强效的急性海马神经毒性。长期接触MC-LR已被证实会导致小鼠学习和记忆缺陷，但MC-LR引起神经毒性的潜在分子机制仍不清楚。在这项研究中，我们观察到 MC-LR 诱导 HT-22 海马神经元氧化应激、线粒体裂变和细胞凋亡。此外，进一步的研究发现，MC-LR 通过激活 Dynamin 相关蛋白 1 (Drp1) 和线粒体裂变因子 (Mff) 诱导线粒体断裂，从而导致海马神经元细胞凋亡。观察到的效应与海马神经元细胞中 MC-LR 暴露导致的细胞内 Ca2+ 增加和蛋白磷酸酶 2A (PP2A) 活性降低有关。 Ca2+ 激活 CaMK II 和 Akt，增强 Drp1 Ser616 残基的磷酸化。抑制 PP2A 活性会增加 AMPK 活性，从而介导 Mff 磷酸化。我们的数据证明，MC-LR 可引起海马神经元线粒体断裂，这为探索 MC-LR 诱导的神经毒性和阿尔茨海默病样变化相关的潜在分子机制提供了新的认识。
Microcystin–leucine–arginine (MC-LR) can cross the blood–brain barrier (BBB) and demonstrate potent acute hippocampal neurotoxicity. Chronic exposure to MC-LR has been confirmed to cause learning and memory deficits in mice, but the potential molecular mechanism of MC-LR-caused neurotoxicity is still unclear. In this research, we observed that MC-LR induced oxidative stress, mitochondrial fission and apoptosis in HT-22 hippocampal neurons. Moreover, further studies identified that MC-LR induced mitochondrial fragmentation via activating Dynamin-related protein 1 (Drp1) and Mitochondrial fission factor (Mff), contributing to apoptosis of hippocampal neuronal cells. The observed effects were associated with increased intracellular Ca2+and reduced activity of protein phosphatases 2A (PP2A) as results of MC-LR exposure in hippocampal neuron cells. Ca2+activates CaMK II and Akt to enhance phosphorylation of Drp1 at Ser616 residue. Inhibition of PP2A activity increased AMPK activity to mediate phosphorylation of Mff. Our data proved that MC-LR can cause mitochondrial fragmentation in hippocampal neurons, which provides novel perception to explore the underlying molecular mechanism associated with MC-LR-induced neurotoxicity and Alzheimer’s disease-like changes.