Methylmercury induces lysosomal membrane permeabilization through JNK-activated Bax lysosomal translocation in neuronal cells

Lin, Tao; Huang, Dingbang; Xiao, Chen; Meng, Xiang‐Jin; Zou, Fei; Wang, Bin

doi:10.1016/j.toxlet.2021.12.021

Cited by 5 publications

(9 citation statements)

References 39 publications

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“…LMP releases cathepsin from the lysosome to cytoplasm, such as CTSB . As shown in Figure , to determine the lysosomal release of CTSB, we employ the protein expression of CTSB and immunofluorescence staining to identify the expression level and CTSB location.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, ROS is also a known factor for disrupting lysosomal membrane integrity as well as causing LMP. , LMP is characterized by the cell membrane integrity loss and leakage into the cytoplasm of intralysosomal enzymes, such as CTSB . First, we detect the LAMP1 expression.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, decreased LTR fluorescence can be an indicator of elevated lysosomal pH, as well as LMP . AO staining is used to detect LMP in AML12 cells . As shown in Figure B, LTR staining is significantly abolished by PA by eliminating lysosomal acidification, while apigenin alters the above appearance.…”

Section: Resultsmentioning

confidence: 99%

“…LMP releases cathepsin from the lysosome to cytoplasm, such as CTSB. 16 As shown in Figure 9, to determine the lysosomal release of CTSB, we employ the protein expression of CTSB and immunofluorescence staining to identify the expression level and CTSB location. As seen in Figure 9A, in contrast to the control group, the PA group had significantly greater levels of CTSB expression (P < 0.01), whereas apigenin lowers it.…”

Section: Apigenin Clears Pa-stimulated Mitochondria Damage Through Ac...mentioning

confidence: 99%

“…According to studies, CTSB can induce pyroptosis if it leaks into the cytosol via LMP . LMP is characterized by the membrane integrity perturbation as well as the leakage into the cytoplasm of intralysosomal enzymes, such as CTSB . As a novel mechanism for activating the NLRP3 inflammasome, the lysosomal CTSB pathway has been proposed .…”

Section: Introductionmentioning

confidence: 99%

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Apigenin Alleviated High-Fat-Diet-Induced Hepatic Pyroptosis by Mitophagy-ROS-CTSB-NLRP3 Pathway in Mice and AML12 Cells

Meng

Gao

Wang

et al. 2023

J. Agric. Food Chem.

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Apigenin is considered the most-known natural flavonoid and is abundant in a wide variety of fruits and vegetables. A high fat diet (HFD) can induce liver injury and hepatocyte death in multiple ways. Pyroptosis is an innovative type of programmed cell death. Moreover, excessive pyroptosis of hepatocytes leads to liver injury. We used HFD to induce liver cell pyroptosis in C57BL/6J mice in this work. After gavage of apigenin, apigenin can significantly reduce the level of lactate dehydrogenase (LDH) in liver tissue ignited by HFD and reduce the levels of NLRP3 (NOD-like receptor family pyrin domain containing 3), the N-terminal domain of GSDMD (GSDMD-N), cleaved-caspase 1, cathepsin B (CTSB), interleukin-1β (IL-1β) and interleukin-18 (IL-18) protein expression and the colocalization of NLRP3 and CTSB and increase the level of lysosomal associated membrane protein-1 (LAMP-1) protein expression, thus alleviating cell pyroptosis. In a further in vitro mechanism study, we find that palmitic acid (PA) can induce pyroptosis in AML12 cells. After adding apigenin, apigenin can clear the damaged mitochondria through mitophagy and reduce the generation of intracellular reactive oxygen species (ROS), thus alleviating CTSB release caused by lysosomal membrane permeabilization (LMP), reducing the LDH release caused by PA and reducing the levels of NLRP3, GSDMD-N, cleaved-caspase 1, CTSB, IL-1β, and IL-18 protein expression. By adding the mitophagy inhibitor cyclosporin A (CsA), LC3-siRNA, the CTSB inhibitor CA-074 methyl ester (CA-074 Me), and the NLRP3 inhibitor MCC950, the aforementioned results were further confirmed. Therefore, our results show that HFD-fed and PA can damage mitochondria, promote the production of intracellular ROS, enhance the lysosomal membrane permeabilization (LMP), and cause the leakage of CTSB, thus activating the NLRP3 inflammatory body and inducing pyroptosis in C57BL/6J mice and AML12 cells, while apigenin alleviates this phenomenon through the mitophagy-ROS-CTSB-NLRP3 pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Apigenin Clears Pa-stimulated Mitochondria Damage Through Ac...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Apigenin Alleviated High-Fat-Diet-Induced Hepatic Pyroptosis by Mitophagy-ROS-CTSB-NLRP3 Pathway in Mice and AML12 Cells

Meng

Gao

Wang

et al. 2023

J. Agric. Food Chem.

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TFEB ameliorates DEHP‐induced neurotoxicity by activating GAL3/TRIM16 axis dependent lysophagy and alleviating lysosomal dysfunction

Xing,

Xu,

et al. 2024

Environmental Toxicology

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Di‐(2‐ethylhexyl) phthalate (DEHP) is a commonly used plasticizer with known neurotoxic effects. However, the specific mechanism underlying this neurotoxicity remains unclear. This study aimed to investigate the role of lysosomal function and lysophagy in DEHP‐induced neurotoxicity, with a particular focus on the regulatory role of Transcription factor EB (TFEB). To achieve this, we utilized in vitro models of DEHP‐exposed SH‐SY5Y cells and HT22 cells. Our findings revealed that DEHP exposure led to lysosomal damage and dysfunction. Moreover, we observed impaired autophagic degradation, characterized by elevated levels of LC3II and p62. DEHP treatment downregulated the expression of TFEB, GAL3, and TRIM16, while upregulating the expression of PARP. This led to the inhibition of GAL3/TRIM16 axis dependent lysophagy and ultimately excessive apoptosis in neuronal cells. Importantly, TFEB overexpression alleviated lysosomal dysfunction, activated lysophagy, and mitigated DEHP‐induced apoptosis. Overall, our results suggest that DEHP induces not only lysosomal dysfunction, but also inhibits lysophagy through the suppression of GAL3/TRIM16 axis. Consequently, impaired clearance of damaged lysosomes occurs, culminating in neuronal apoptosis. Taken together, our findings highlight the critical role of TFEB in regulating lysophagy and lysosomal function. Furthermore, TFEB may serve as a potential therapeutic target for mitigating DEHP‐induced neuronal toxicity.

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Mechanism of vitamin B6 benzoyl hydrazone platinum(II) complexes overcomes multidrug resistance in lung cancer

Zheng

et al. 2022

European Journal of Medicinal Chemistry

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Methylmercury induces lysosomal membrane permeabilization through JNK-activated Bax lysosomal translocation in neuronal cells

Cited by 5 publications

References 39 publications

Apigenin Alleviated High-Fat-Diet-Induced Hepatic Pyroptosis by Mitophagy-ROS-CTSB-NLRP3 Pathway in Mice and AML12 Cells

Apigenin Alleviated High-Fat-Diet-Induced Hepatic Pyroptosis by Mitophagy-ROS-CTSB-NLRP3 Pathway in Mice and AML12 Cells

TFEB ameliorates DEHP‐induced neurotoxicity by activating GAL3/TRIM16 axis dependent lysophagy and alleviating lysosomal dysfunction

Mechanism of vitamin B6 benzoyl hydrazone platinum(II) complexes overcomes multidrug resistance in lung cancer

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