Suggested mechanism by which lysosomotropic agents (here exemplified by mefloquine) induce granule membrane permeabilization and apoptosis in MCs. (1) Accumulation of mefloquine inside the granules. Mefloquine, a weakly basic compound, can in its unprotonated form passively diffuse through the MC plasma and granule membranes. In the acidic interior of granules, mefloquine becomes protonated and can no longer pass through the membrane, thus accumulating inside the granules. (2) Granule membrane permeabilization. When the mefloquine concentration reaches a certain threshold, mefloquine acquires detergent-like properties and induces granule membrane damage and permeabilization. (3) Induction of oxidative stress within granules. Hydrogen peroxide (H2O2) freely diffuses into the granules. In the granules, the acidic pH and the presence of free iron promote the oxidation of iron and the generation of ROS such as hydroxyl radicals (HO•) via Fenton-type reactions. The electrostatic interaction between negatively charged serglycin and cationic iron likely participates in maintaining the iron pool within MC granules, thus contributing to the generation of ROS. The generated ROS cause further destabilization of granule membranes leading to the release of many granule components into the cytosol. Granzyme B also participates in induction of ROS production upon exposure to mefloquine. (4) Release of granule contents into the cytosol. Due to the granule permeabilization, granule contents (e.g., fully active proteases in complex with serglycin, ROS and iron) enter the cytosol. (5, 6) Induction of apoptosis. Mefloquine-induced granule permeabilization and the subsequent translocation of the granule contents to the cytosol induce apoptosis manifested by phosphatidylserine externalization and DNA degradation. The MC proteases, such as tryptase and granzyme B, may participate in apoptosis in response to mefloquine. BAF, bafilomycin-A1; DFO, deferoxamine mesylate; Gnz B, granzyme B; NAC, N-acetylcysteine; ROS, reactive oxygen species.