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Lysosomal membrane permeabilization (LMP) is implicated in cancer cell death. However, its role and mechanism of action in neuronal death remain to be established. In the present study, we investigate the function of cellular zinc in oxidative stress-induced LMP using hippocampal neurons. Live-cell confocal microscopy with FluoZin-3 fluorescence showed that H(2)O(2) exposure induced vesicles containing labile zinc in hippocampal neurons. Double staining with LysoTracker or MitoTracker disclosed that the majority of the zinc-containing vesicles were lysosomes and not mitochondria. H(2)O(2) additionally augmented the 4-hydroxy-2-nonenal (HNE) adduct level in lysosomes. Intracellular zinc chelation with TPEN [tetrakis(2-pyridylmethyl)ethylenediamine] completely blocked both HNE accumulation and neuronal death. Interestingly, within 1 h after the onset of H(2)O(2) exposure, some of zinc-loaded vesicles lost their zinc signals. Consistent with the characteristics of LMP, a lysosomal enzyme, cathepsin D, was released into the cytosol, and cathepsin inhibitors partially rescued neuronal death. We further examined the possibility that HNE or zinc mediates H(2)O(2)-triggered LMP. Similar to H(2)O(2), exposure to HNE or zinc triggered lysosomal zinc accumulation and LMP. Moreover, isolated lysosomes underwent LMP when exposed to HNE or zinc, but not H(2)O(2), supporting the direct mediation of LMP by HNE and/or zinc. The appearance of zinc-containing vesicles and the increases in levels of cathepsin D and HNE, were also observed in hippocampal neurons of rats after kainate seizures. Thus, under oxidative stress, neuronal lysosomes accumulate zinc and HNE, and eventually undergo LMP, which may constitute a key mechanism of oxidative neuronal death.

Zinc and 4-Hydroxy-2-Nonenal Mediate Lysosomal Membrane Permeabilization Induced by H2O2in Cultured Hippocampal Neurons

Zinc and 4-Hydroxy-2-Nonenal Mediate Lysosomal Membrane Permeabilization Induced by H₂O₂in Cultured Hippocampal Neurons