Zn²⁺ efflux through lysosomal exocytosis prevents Zn²⁺-induced toxicity

Zn²⁺ is an essential micronutrient and an important ionic signal whose excess, as well as scarcity, is detrimental to cells. Free cytoplasmic Zn²⁺ is controlled by a network of Zn²⁺ transporters and chelating proteins. Recently, lysosomes became the focus of studies in Zn²⁺ transport, as they were shown to play a role in Zn²⁺-induced toxicity by serving as Zn²⁺ sinks that absorb Zn²⁺ from the cytoplasm. Here, we investigated the impact of the lysosomal Zn²⁺ sink on the net cellular Zn²⁺ distribution and its role in cell death. We found that lysosomes played a cytoprotective role during exposure to extracellular Zn²⁺. Such a role required lysosomal acidification and exocytosis. Specifically, we found that the inhibition of lysosomal acidification using Bafilomycin A1 (Baf) led to a redistribution of Zn²⁺ pools and increased apoptosis. Additionally, the inhibition of lysosomal exocytosis through knockdown (KD) of the lysosomal SNARE proteins VAMP7 and synaptotagmin VII (SYT7) suppressed Zn²⁺ secretion and VAMP7 KD cells had increased apoptosis. These data show that lysosomes play a central role in Zn²⁺ handling, suggesting that there is a new Zn²⁺ detoxification pathway.