Zn2+ efflux through lysosomal exocytosis prevents Zn2+-induced toxicity.
Zn(2+) is an essential micronutrient and an important ionic signal whose excess, as well as scarcity, is detrimental to cells. Free cytoplasmic Zn(2+) is controlled by a network of Zn(2+) transporters and chelating proteins. Recently, lysosomes became the focus of studies in Zn(2+) transport, as they were shown to play a role in Zn(2+)-induced toxicity by serving as Zn(2+) sinks that absorb Zn(2+) from the cytoplasm. Here, we investigated the impact of the lysosomal Zn(2+) sink on the net cellular Zn(2+) distribution and its role in cell death. We found that lysosomes played a cytoprotective role during exposure to extracellular Zn(2+). 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(2+) 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(2+) secretion and VAMP7 KD cells had increased apoptosis. These data show that lysosomes play a central role in Zn(2+) handling, suggesting that there is a new Zn(2+) detoxification pathway.
The Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Ira
I
Kukic
The Department of Nutritional Sciences, College of Health and Human Development, The Pennsylvania State University, University Park, PA 16802, USA Department of Surgery, Penn State Hershey Medical Center, Hershey, PA 17033, USA Department of Cellular and Molecular Physiology, Penn State Hershey Medical Center, Hershey, PA 17033, USA.
Shannon L
SL
Kelleher
The Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA kiselyov@pitt.edu.
Kirill
K
Kiselyov
D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D018942:Macrolides / Q000494:pharmacology; D014162:Transfection; D015032:Zinc / Q000378:metabolism* / Q000633:toxicity*
D018942:Macrolides; C040929:bafilomycin A1; D015032:Zinc
Exocytosis; Golgi; Lysosome; Metallothionein; Slc30a; Zinc; Zn2+ transport; ZnT