Cadmium Impairs Autophagy Leading to Apoptosis by Ca(2+)-Dependent Activation of JNK Signaling Pathway in Neuronal Cells.
Cadmium Impairs Autophagy Leading to Apoptosis by Ca(2+)-Dependent Activation of JNK Signaling Pathway in Neuronal Cells.
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镉会损害自噬，通过 Ca2+ 依赖性激活神经元细胞中的 JNK 信号通路导致细胞凋亡
DOI：
10.1007/s11064-021-03341-x
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发表时间：
2021-08
影响因子：
4.4
通讯作者：
Chen, Long
中科院分区：
文献类型：
--
作者：
Xu, Chong;Chen, Sujuan;Xu, Ming;Chen, Xiaoling;Wang, Xiaoxue;Zhang, Hai;Dong, Xiaoqing;Zhang, Ruijie;Chen, Xin;Gao, Wei;Huang, Shile;Chen, Long
自噬是细胞内成分和功能失调的细胞器的自我降解过程，与神经退行性疾病密切相关。研究表明，镉 (Cd) 部分通过损害自噬而引起神经毒性。然而，其根本机制尚未完全阐明。在这项研究中，我们发现，Cd 会诱导 PC12 细胞和原代小鼠神经元中自噬体的扩张，并伴随自噬相关 (Atg) 蛋白的异常表达。 3-MA 是一种经典的自噬抑制剂，可减弱 Cd 诱导的自噬体扩张和细胞凋亡。进一步研究表明，Cd 激活 JNK 通路，导致自噬体扩张依赖性神经元凋亡。这一发现得到了以下发现的支持：用 SP600125 药理抑制 JNK 或显性失活 c-Jun 的表达显着减弱 Cd 诱导的自噬体扩张和 Atg 蛋白的异常表达，以及 PC12 细胞和/或原代神经元的凋亡。此外，我们注意到，用 BAPTA/AM 螯合细胞内游离 Ca2+([Ca2+]i) 可以显着阻断 Cd 引起的 JNK 通路激活，进而阻断自噬体的扩张、Atg 蛋白的异常表达以及神经元细胞的凋亡。用 EGTA 或 2-APB 预防 [Ca2+] 升高后也观察到类似的事件，这意味着涉及 Ca2+ 依赖性机制。综上所述，结果表明，Cd 会损害自噬，通过 Ca2+ 依赖性激活神经元细胞中的 JNK 信号通路而导致细胞凋亡。我们的研究结果强调，通过控制细胞内 Ca2+ 水平和/或 JNK 活性来改善自噬可能是对抗 Cd 诱导的神经毒性和神经变性的一种有希望的干预措施。
Autophagy, a process for self-degradation of intracellular components and dysfunctional organelles, is closely related with neurodegenerative diseases. It has been shown that cadmium (Cd) induces neurotoxicity partly by impairing autophagy. However, the underlying mechanism is not fully elucidated. In this study, we show that Cd induced expansion of autophagosomes with a concomitant abnormal expression of autophagy-related (Atg) proteins in PC12 cells and primary murine neurons. 3-MA, a classical inhibitor of autophagy, attenuated Cd-induced expansion of autophagosomes and apoptosis in the cells. Further investigation demonstrated that Cd activated JNK pathway contributing to autophagosome expansion-dependent neuronal apoptosis. This is supported by the findings that pharmacological inhibition of JNK with SP600125 or expression of dominant negative c-Jun markedly attenuated Cd-induced expansion of autophagosomes and abnormal expression of Atg proteins, as well as apoptosis in PC12 cells and/or primary neurons. Furthermore, we noticed that chelating intracellular free Ca2+([Ca2+]i) with BAPTA/AM profoundly blocked Cd-elicited activation of JNK pathway and consequential expansion of autophagosomes, abnormal expression of Atg proteins, and apoptosis in the neuronal cells. Similar events were also seen following prevention of [Ca2+]ielevation with EGTA or 2-APB, implying a Ca2+-dependent mechanism involved. Taken together, the results indicate that Cd impairs autophagy leading to apoptosis by Ca2+-dependent activation of JNK signaling pathway in neuronal cells. Our findings highlight that manipulation of intracellular Ca2+level and/or JNK activity to ameliorate autophagy may be a promising intervention against Cd-induced neurotoxicity and neurodegeneration.
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影响因子：
21.3
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影响因子：
4.7
作者：
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影响因子：
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作者：
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