Pb disrupts autophagic flux through inhibiting the formation and activity of lysosomes in neural cells
Lead (Pb) has long been known as a metallic toxin to exert detrimental effects on human health, particularly on the central nervous system (CNS). Misregulated autophagy was regularly associated with multiple cellular dysfunctions and human diseases. However, the role of autophagy underlying Pb-induc...
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Veröffentlicht in: | Toxicology in vitro 2019-03, Vol.55, p.43-50 |
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Sprache: | eng |
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Zusammenfassung: | Lead (Pb) has long been known as a metallic toxin to exert detrimental effects on human health, particularly on the central nervous system (CNS). Misregulated autophagy was regularly associated with multiple cellular dysfunctions and human diseases. However, the role of autophagy underlying Pb-induced neurotoxicity remains to be elucidated. In this study, we demonstrated that Pb promoted the accumulation of autophagosomes in PC12 cells, and subsequent findings revealed that this autophagosome accumulation was primarily caused by the inhibition of autophagic flux. Moreover, the results showed that Pb affected autophagy course through increasing Beclin 1 and ATG5 expression levels. Specifically, by double labeling with LC3-II (a marker of autophagosome) and LAMP-1 (a marker of lysosome), Pb impaired fusion between autophagosomes and lysosomes. Additionally, Pb exposure significantly reduced the number or size of lysosomes via decreasing the level of LAMP1, which is confirmed by the LysoTracker Red staining. Furthermore, the impairment of lysosomal activity was also signaled by the altered pH value of this acidic organelle. Overall, Pb exposure led to injuries of autophagy of neural cells through inhibiting the genesis and activity of lysosomes. The data provides insight with the neurotoxicity of Pb in a novel perspective, autophagy.
•Pb induced cell autophagy in a dose- and time-dependent manner in PC12 cells.•Pb inhibited autophagic flux through blocking the degradation circle of autophagosomes.•Pb impaired the function of lysosomes. |
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ISSN: | 0887-2333 1879-3177 |
DOI: | 10.1016/j.tiv.2018.11.010 |