Contribution of particle‐induced lysosomal membrane hy-perpolarization to lysosomal membrane permeabilization

Tahereh Ziglari, Zifan Wang, Andrij Holian

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13 Scopus citations


Lysosomal membrane permeabilization (LMP) has been proposed to precede nanoparti-cle‐induced macrophage injury and NLRP3 inflammasome activation; however, the underlying mechanism(s) of LMP is unknown. We propose that nanoparticle‐induced lysosomal hyperpolarization triggers LMP. In this study, a rapid non‐invasive method was used to measure changes in lysosomal membrane potential of murine alveolar macrophages (AM) in response to a series of nanoparticles (ZnO, TiO2, and CeO2). Crystalline SiO2 (micron‐sized) was used as a positive control. Changes in cytosolic potassium were measured using Asante potassium green 2. The results demonstrated that ZnO or SiO2 hyperpolarized the lysosomal membrane and decreased cytosolic potassium, suggesting increased lysosome permeability to potassium. Time‐course experiments revealed that lysosomal hyperpolarization was an early event leading to LMP, NLRP3 activation, and cell death. In contrast, TiO2‐ or valinomycin‐treated AM did not cause LMP unless high doses led to lysosomal hyperpolarization. Neither lysosomal hyperpolarization nor LMP was observed in CeO2‐ treated AM. These results suggested that a threshold of lysosomal membrane potential must be exceeded to cause LMP. Furthermore, inhibition of lysosomal hyperpolarization with Bafilomycin A1 blocked LMP and NLRP3 activation, suggesting a causal relation between lysosomal hyperpolarization and LMP.

Original languageEnglish
Article number2277
Pages (from-to)1-19
Number of pages19
JournalInternational Journal of Molecular Sciences
Issue number5
StatePublished - Mar 1 2021


  • Crystalline silica
  • Lysosomal membrane potential
  • Nanoparticles
  • Zinc oxide nanoparticles


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