mn诱导SK-N-SH细胞线粒体损伤、PINK1/Parkin表达和线粒体自噬的双相剂量反应

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS ACS Applied Bio Materials Pub Date : 2023-04-01 DOI:10.1177/15593258231169392
Yue Zhang, Hong-Tao Hu, Yu-Min Cao, Zhi-Gang Jiang, Jie Liu, Qi-Yuan Fan
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引用次数: 1

摘要

过量的锰(Mn)暴露产生线粒体损伤的神经毒性。线粒体自噬是一种消除受损线粒体以保护细胞的保护机制。本研究的目的是确定mn诱导线粒体损伤的剂量反应,多巴胺产生的SK-N-SH细胞中线粒体自噬介导蛋白PINK1/Parkin的表达和线粒体自噬。将细胞分别暴露于0、300、900和1500 μM的Mn2+中24 h,观察ROS生成、线粒体损伤和线粒体自噬情况。ELISA法检测多巴胺水平,western blot法检测神经毒性和线粒体自噬相关蛋白(α-synuclein、PINK1、Parkin、optinurin、LC3II/I)水平。Mn增加细胞内ROS和凋亡,降低线粒体膜电位呈浓度依赖性。然而,在低剂量300 μM Mn下,自噬体增加了11倍,而在高剂量1500 μM下,自噬体减少了4倍,同时线粒体自噬介导的蛋白PINK1/Parkin和LC3II/I比值降低,optinurin表达增加,导致α-突触核蛋白积累增加,多巴胺产生减少。因此,mn诱导的线粒体自噬表现出一种新的双相调节:在低剂量下,线粒体自噬被激活以消除受损的线粒体,然而,在高剂量下,细胞逐渐丧失适应机制,PINK1/ parkinson介导的线粒体自噬减弱,导致神经毒性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Biphasic Dose-Response of Mn-Induced Mitochondrial Damage, PINK1/Parkin Expression, and Mitophagy in SK-N-SH Cells.

Excessive manganese (Mn) exposure produces neurotoxicity with mitochondrial damage. Mitophagy is a protective mechanism to eliminate damaged mitochondria to protect cells. The aim of this study was to determine the dose-response of Mn-induced mitochondria damage, the expression of mitophagy-mediated protein PINK1/Parkin and mitophagy in dopamine-producing SK-N-SH cells. Cells were exposed to 0, 300, 900, and 1500 μM Mn2+ for 24 h, and ROS production, mitochondrial damage and mitophagy were examined. The levels of dopamine were detected by ELISA and neurotoxicity and mitophagy-related proteins (α-synuclein, PINK1, Parkin, Optineurin, and LC3II/I) were detected by western blot. Mn increased intracellular ROS and apoptosis and decreased mitochondrial membrane potential in a concentration-dependent manner. However, at the low dose of 300 μM Mn, autophagosome was increased 11-fold, but at the high dose of 1500 μM, autophagosome was attenuated to 4-fold, together with decreased mitophagy-mediated protein PINK1/Parkin and LC3II/I ratio and increased Optineurin expression, resulting in increased α-synuclein accumulation and decreased dopamine production. Thus, Mn-induced mitophagy exhibited a novel biphasic regulation: at the low dose, mitophagy is activated to eliminate damaged mitochondria, however, at the high dose, cells gradually loss the adaptive machinery, the PINK1/Parkin-mediated mitophagy weakened, resulting in neurotoxicity.

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来源期刊
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
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