Cu(II) disrupts autophagy-mediated lysosomal degradation of oligomeric Aβ in microglia via mTOR-TFEB pathway

Tan, Xiaofang; Guan, Huifeng; Yang, Yang; Luo, Shenying; Hou, Liang; Chen, Hongzhuan; Li, Juan

doi:10.1016/j.taap.2020.115090

Cited by 14 publications

(9 citation statements)

References 42 publications

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“…Recent studies have shown that uncontrolled or overstimulated autophagy may intermediate cell death. Reports prove that Cu can serve as one new autophagy stimulator [ 34 , 35 ]. Whereas, it is still unknown if autophagy is related to Cu reproduction toxicity.…”

Section: Discussionmentioning

confidence: 99%

Induction of autophagy via the ROS-dependent AMPK-mTOR pathway protects copper-induced spermatogenesis disorder

et al. 2022

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Copper (Cu) is a necessary micronutrient at lower concentration, while excessive Cu exposure or Cu homeostasis disorders can lead to toxicity. The mechanism of male reproductive toxicity induced by Cu is still unknown. This study aims to investigate whether autophagy plays an important role in copper-induced spermatogenesis disorder in vivo and vitro. The present study showed that copper sulfate (CuSO 4 ) might significantly promote autophagy level in the testis and mouse-derived spermatogonia cell line GC-1 spg cells. Concurrently, CuSO 4 could induce autophagy via AMPK-mTOR pathway that downregulated p -mTOR/mTOR and subsequently upregulated p -AMPKα/AMPKα as well as p -ULK1/ULK1. In the meanwhile, CuSO 4 treatment could also increase expression levels of the autophagy-related proteins. Then, the role of oxidative stress in CuSO 4 -induced autophagy was investigated. The findings demonstrated that oxidative stress inhibitor (NAC) attenuated CuSO 4 -induced autophagy in vivo and vitro , reversing the activation for AMPK-mTOR pathway. Additionally, the study also investigated how autophagy worked under the spermatogenesis disorder induced by CuSO 4 . Inhibition of autophagy could decrease cell viability, and enhance the ROS accumulation and apoptosis in the GC-1 cells, meanwhile, the spermatogenesis disorder, oxidative stress and histopathological changes were increased in the testis. Furthermore, co-treatment with the apoptosis inhibitor (Z-VAD-FMK) could decrease the spermatogenesis disorder but not influence autophagy. Besides, the crosslink between autophagy and ferroptosis were also measured, the data showed that inhibition of autophagy could suppress CuSO 4 -induced ferroptosis in in vivo and vitro . Altogether, abovementioned results indicated that CuSO 4 induced autophagy via oxidative stress-dependent AMPK-mTOR pathway in the GC-1 cells and testis, and autophagy activation possibly led to the generation of protection mechanism through oxidative damage and apoptosis inhibition, however, autophagy also aggravate CuSO 4 toxicology through promoting ferroptosis. Overall, autophagy plays a positive role for attenuating CuSO 4 -induced testicular damage and spermatogenesis disorder. Our study provides a possible targeted therapy for Cu overload-induced reproduction toxicology.

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Section: Discussionmentioning

confidence: 99%

Induction of autophagy via the ROS-dependent AMPK-mTOR pathway protects copper-induced spermatogenesis disorder

et al. 2022

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“…Several recent studies have examined the relationship between copper metabolism and autophagy. Some found that excess copper negatively influenced autophagy and impaired autophagic-lysosome degradation [8,32]. Recent research demonstrated that copper induced autophagy to protect cells from apoptotic cell death [9].…”

Section: Discussionmentioning

confidence: 99%

Direct Interaction of ATP7B and LC3B Proteins Suggests a Cooperative Role of Copper Transportation and Autophagy

Pantoom

Pomorski

Huth

et al. 2021

Cells

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Macroautophagy/autophagy plays an important role in cellular copper clearance. The means by which the copper metabolism and autophagy pathways interact mechanistically is vastly unexplored. Dysfunctional ATP7B, a copper-transporting ATPase, is involved in the development of monogenic Wilson disease, a disorder characterized by disturbed copper transport. Using in silico prediction, we found that ATP7B contains a number of potential binding sites for LC3, a central protein in the autophagy pathway, the so-called LC3 interaction regions (LIRs). The conserved LIR3, located at the C-terminal end of ATP7B, was found to directly interact with LC3B in vitro. Replacing the two conserved hydrophobic residues W1452 and L1455 of LIR3 significantly reduced interaction. Furthermore, autophagy was induced in normal human hepatocellular carcinoma cells (HepG2) leading to enhanced colocalization of ATP7B and LC3B on the autophagosome membranes. By contrast, HepG2 cells deficient of ATP7B (HepG2 ATP7B−/−) showed autophagy deficiency at elevated copper condition. This phenotype was complemented by heterologous ATP7B expression. These findings suggest a cooperative role of ATP7B and LC3B in autophagy-mediated copper clearance.

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“…Several recent studies examined the relationship between copper metabolism and autophagy. Some found that excess copper negatively influenced autophagy and impaired autophagic-lysosome degradation [9], [31]. Recent research demonstrated that cop-per induced autophagy to protect cells from apoptotic cell death [9].…”

Section: Discussionmentioning

confidence: 99%

Direct Interaction of ATP7B and LC3B Proteins Suggests a Cooperative Role of Copper Transportation and Autophagy

Pantoom¹,

Pomorski²,

Huth³

et al. 2021

Preprint

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Macroautophagy/autophagy plays an important role in cellular copper clearance. The means by which the copper metabolism and autophagy pathways interact mechanistically is vastly unexplored. Dysfunctional ATP7B, a copper-transporting ATPase, is involved in the development of monogenic Wilson disease, a disorder characterized by disturbed copper transport. Using in silico prediction, we found that ATP7B contains a number of potential binding sites for LC3, a central protein in autophagy pathway, so-called LC3 interaction regions (LIRs). The conserved LIR3, located at the C-terminal end of ATP7B, was found to directly interact with LC3B in vitro. Replacing the two conserved hydrophobic residues W1452 and L1455 of LIR3 significantly reduced interaction. Furthermore, autophagy was induced in normal human hepatocellular carcinoma cells (HepG2) leading to enhanced colocalization of ATP7B and LC3B on the autophagosome membranes. By contrast, HepG2 cells deficient of ATP7B (HepG2 ATP7B-/-) showed autophagy deficiency at elevated copper condition. This phenotype was complemented by heterologous ATP7B expression. These findings suggest a cooperative role of ATP7B and LC3B in autophagy-mediated copper clearance.

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Cu(II) disrupts autophagy-mediated lysosomal degradation of oligomeric Aβ in microglia via mTOR-TFEB pathway

Cited by 14 publications

References 42 publications

Induction of autophagy via the ROS-dependent AMPK-mTOR pathway protects copper-induced spermatogenesis disorder

Induction of autophagy via the ROS-dependent AMPK-mTOR pathway protects copper-induced spermatogenesis disorder

Direct Interaction of ATP7B and LC3B Proteins Suggests a Cooperative Role of Copper Transportation and Autophagy

Direct Interaction of ATP7B and LC3B Proteins Suggests a Cooperative Role of Copper Transportation and Autophagy

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