PMID- 24829149
OWN - NLM
STAT- MEDLINE
DCOM- 20150420
LR  - 20220223
IS  - 1477-9137 (Electronic)
IS  - 0021-9533 (Print)
IS  - 0021-9533 (Linking)
VI  - 127
IP  - Pt 14
DP  - 2014 Jul 15
TI  - Zn2+ efflux through lysosomal exocytosis prevents Zn2+-induced toxicity.
PG  - 3094-103
LID - 10.1242/jcs.145318 [doi]
AB  - 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.
CI  - (c) 2014. Published by The Company of Biologists Ltd.
FAU - Kukic, Ira
AU  - Kukic I
AD  - The Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 
      15260, USA.
FAU - Kelleher, Shannon L
AU  - Kelleher SL
AD  - 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.
FAU - Kiselyov, Kirill
AU  - Kiselyov K
AD  - The Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 
      15260, USA kiselyov@pitt.edu.
LA  - eng
GR  - HD058577/HD/NICHD NIH HHS/United States
GR  - R01 HD058577/HD/NICHD NIH HHS/United States
GR  - P30 CA047904/CA/NCI NIH HHS/United States
GR  - P30CA047904/CA/NCI NIH HHS/United States
GR  - ES01678/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140514
PL  - England
TA  - J Cell Sci
JT  - Journal of cell science
JID - 0052457
RN  - 0 (Macrolides)
RN  - 88899-55-2 (bafilomycin A1)
RN  - J41CSQ7QDS (Zinc)
SB  - IM
MH  - Cell Death/drug effects/physiology
MH  - Exocytosis/drug effects/*physiology
MH  - HeLa Cells
MH  - Humans
MH  - Lysosomes/*metabolism
MH  - Macrolides/pharmacology
MH  - Transfection
MH  - Zinc/*metabolism/*toxicity
PMC - PMC4095854
OTO - NOTNLM
OT  - Exocytosis
OT  - Golgi
OT  - Lysosome
OT  - Metallothionein
OT  - Slc30a
OT  - Zinc
OT  - Zn2+ transport
OT  - ZnT
EDAT- 2014/05/16 06:00
MHDA- 2015/04/22 06:00
PMCR- 2015/07/15
CRDT- 2014/05/16 06:00
PHST- 2014/05/16 06:00 [entrez]
PHST- 2014/05/16 06:00 [pubmed]
PHST- 2015/04/22 06:00 [medline]
PHST- 2015/07/15 00:00 [pmc-release]
AID - jcs.145318 [pii]
AID - 10.1242/jcs.145318 [doi]
PST - ppublish
SO  - J Cell Sci. 2014 Jul 15;127(Pt 14):3094-103. doi: 10.1242/jcs.145318. Epub 2014 
      May 14.