Study of mitophagy and ATP-related metabolomics based on β-amyloid levels in Alzheimer's disease
Study of mitophagy and ATP-related metabolomics based on β-amyloid levels in Alzheimer's disease
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基于阿尔茨海默病β-淀粉样蛋白水平的线粒体自噬和 ATP 相关代谢组学研究
DOI：
10.1016/j.yexcr.2020.112266
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发表时间：
2020-11-01
影响因子：
3.7
通讯作者：
Li, Yu
中科院分区：
文献类型：
--
作者：
Xiong, Xiaomin;Li, Shijie;Li, Yu
阿尔茨海默病（AD）中β -淀粉样蛋白（A β）肽的聚集以线粒体功能障碍和线粒体自噬损伤为特征。线粒体自噬是一种自我平衡机制，通过自噬选择性地消除受损的线粒体。Valinomycin是一种呼吸链抑制剂，通过PINK1/Parkin信号通路激活线粒体自噬。然而，有丝分裂和缬霉素在A β形成中的关联机制尚未被探索。在这里，我们证明转基因（N2a/APP695swe）细胞过表达突变淀粉样前体蛋白（APP）可作为AD的体外模型，用于研究线粒体自噬和atp相关代谢组学。我们的研究结果证明，valinomycin诱导N2a/APP695swe细胞线粒体自噬激活的时间依赖性增加，表现为PINK1、Parkin和LC3II水平的增加，以及帕金森-Tom20共定位的增加和线粒体数量的减少（表现为Tom20水平的降低）。缬霉素在治疗3 h后显著降低A β(1-42)和A β(1-40)水平。此时，ATP水平和ATP相关代谢物显著升高。我们的研究结果表明，通过valinomycin诱导的线粒体自噬消除受损的线粒体通过降低A β和提高ATP水平来改善AD。
The aggregation of beta-amyloid (A beta) peptide in Alzheimer's disease (AD) is characterized by mitochondrial dysfunction and mitophagy impairment. Mitophagy is a homeostatic mechanism by which autophagy selectively eliminates damaged mitochondria. Valinomycin is a respiratory chain inhibitor that activates mitophagy via the PINK1/Parkin signaling pathway. However, the mechanism underlying the association between mitophagy and valinomycin in A beta formation has not been explored. Here, we demonstrate that genetically modified (N2a/APP695swe) cells overexpressing a mutant amyloid precursor protein (APP) serve as an in vitro model of AD for studying mitophagy and ATP-related metabolomics. Our results prove that valinomycin induced a time-dependent increase in the mitophagy activation of N2a/APP695swe cells as indicated by increased levels of PINK1, Parkin, and LC3II as well as increased the colocalization of Parkin-Tom20 and fewer mitochondria (indicated by decreased Tom20 levels). Valinomycin significantly decreased A beta(1-42) and A beta(1-40) levels after 3 h of treatment. ATP levels and ATP-related metabolites were significantly increased at this time. Our findings suggest that the elimination of impaired mitochondria via valinomycin-induced mitophagy ameliorates AD by decreasing A beta and improving ATP levels.