Zn efflux through lysosomal exocytosis prevents Zn-induced toxicity

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