Department of Pharmacology, School of Medicine, Eulji University, Daejeon 34824, Korea.
Int J Mol Sci. 2022 Aug 8;23(15):8811. doi: 10.3390/ijms23158811.
Zinc is a trace metal vital for various functions in nerve cells, although the effect of zinc deficiency on neuronal autophagy remains unclear. This study aimed to elucidate whether zinc deficiency induced by treatment with N, N, N', N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a zinc chelator, affects and alters autophagy activity. In cell viability assays, TPEN showed cytotoxicity in HT-22 cells. TPEN treatment also increased LC3-II levels and the ratio of LC3-II to LC3-I. Western blot analysis showed that phospho-AMP-activated protein kinase levels and the ratio of phospho-AMP-activated protein kinase to total AMP-activated protein kinase increased. Protein levels of the mammalian target of rapamycin and sirtuin 1 decreased following TPEN treatment. When TPEN-treated HT-22 cells were cotreated with autophagy inhibitors, 3-methyladenine (1 mM), or bafilomycin A1 (3 nM), the TPEN-induced decrease in cell viability was exacerbated. Cotreatment with chloroquine (10 μM) partially restored cell viability. The study showed that zinc deficiency induces autophagy and may be cytoprotective in neurons. We expect our results to add a new perspective to our understanding of the neuronal pathology related to zinc deficiency.
锌是一种痕量金属，对神经细胞的各种功能至关重要，尽管锌缺乏对神经元自噬的影响仍不清楚。本研究旨在阐明用锌螯合剂 N，N，N'，N'-四（2-吡啶甲基）乙二胺（TPEN）处理诱导的锌缺乏是否会影响和改变自噬活性。在细胞活力测定中，TPEN 在 HT-22 细胞中表现出细胞毒性。TPEN 处理还增加了 LC3-II 水平和 LC3-II 与 LC3-I 的比值。Western blot 分析显示磷酸化 AMP 激活的蛋白激酶水平和磷酸化 AMP 激活的蛋白激酶与总 AMP 激活的蛋白激酶的比值增加。哺乳动物雷帕霉素靶蛋白和 Sirtuin 1 的蛋白水平在 TPEN 处理后降低。当用自噬抑制剂 3-甲基腺嘌呤（1mM）或巴弗洛霉素 A1（3nM）共同处理 TPEN 处理的 HT-22 细胞时，TPEN 诱导的细胞活力下降加剧。氯喹（10μM）的共处理部分恢复了细胞活力。研究表明，锌缺乏会诱导自噬，并且在神经元中可能具有细胞保护作用。我们希望我们的结果为理解与锌缺乏相关的神经元病理学增加一个新的视角。
