Study of mitophagy and ATP-related metabolomics based on β-amyloid levels in Alzheimer's disease.

• 影响指数: 4.145
• 发表时间: 11 2020 1
• 来源期刊: Exp Cell Res
• DOI: 10.1016/j.yexcr.2020.112266
• PMID: 32905804
• 文章类型: Journal Article
• 中科院分区: Q3
• 方向: 生物
• 作者列表: Xiong X,Li S,Han TL,Zhou F,Zhang X,Tian M,Tang L,Li Y

关键词: Alzheimer's disease; Metabolomic; Mitophagy; N2a/APP695swe cells; Valinomycin

Mesh: Adenosine Triphosphate / biosynthesis; Alzheimer Disease / genetics metabolism pathology; Amyloid beta-Peptides / genetics metabolism; Amyloid beta-Protein Precursor / genetics metabolism pharmacology; Animals; Cell Line, Tumor; Gene Expression Regulation; Humans; Ionophores / pharmacology; Membrane Potential, Mitochondrial / drug effects; Membrane Transport Proteins / genetics metabolism; Metabolomics / methods; Mice; Microtubule-Associated Proteins / genetics metabolism; Mitochondria / drug effects metabolism pathology; Mitochondrial Precursor Protein Import Complex Proteins; Mitophagy / drug effects genetics; Models, Biological; Neurons / drug effects metabolism pathology; Peptide Fragments / genetics metabolism; Protein Kinases / genetics metabolism; Receptors, Cell Surface / genetics metabolism; Ubiquitin-Protein Ligases / genetics metabolism; Valinomycin / pharmacology

Abstract

The aggregation of β-amyloid (Aβ) 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 Aβ 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 Aβ1-42 and Aβ1-40 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 Aβ and improving ATP levels.