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Perturbation of intracellular K(+) homeostasis with valinomycin promotes cell death by mitochondrial swelling and autophagic processes.
MedLine Citation:
PMID:  21877215     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Perturbation of cellular K(+) homeostasis is a common motif in apoptosis but it is unknown whether a decrease in intracellular K(+) alone is sufficient to replicate apoptotic hallmarks. We investigated, which mode of cell death is induced by decreasing the intracellular K(+) concentration using valinomycin, a highly K(+)-selective ionophore. Valinomycin treatment induced mitochondrial swelling and minor nuclear changes in cell lines (BV-2, C6, HEK 293), and in primary mouse microglia and astrocytes. In the microglial cell line BV-2, we identified and quantified three phenotypes in valinomycin-exposed cells. The first and most prevalent phenotype (62 ± 2%) was characterized by swollen mitochondria and no chromatin condensation, and the second (25 ± 3%) by swollen mitochondria and slight chromatin condensation. Only the third phenotype (11 ± 4%) fulfilled criteria of apoptosis by having normal-sized mitochondria and strongly condensed chromatin. Valinomycin-induced swelling of mitochondria was not altered by the adenine nucleotide translocase inhibitor bongkrekic acid (BA), the pan caspase inhibitor Z-VAD-FMK, changing extracellular K(+) or Cl(-) concentrations, or the membrane-permeable Ca(2+) chelator BAPTA-AM. Only co-exposure of cells to valinomycin and the Ca(2+) ionophore ionomycin in high K(+) Cl(-)-free extracellular solution suppressed mitochondrial swelling. Ionomycin alone caused shrinkage of mitochondria. Additionally, valinomycin promoted autophagic processes, which were further enhanced by preincubation with BA or with Z-VAD-FMK. Valinomycin-dependent chromatin condensation was inhibited by BA, Z-VAD-FMK, BAPTA-AM, and ionomycin. Our findings demonstrate that mitochondrial swelling and autophagy are common features of valinomycin-exposed cells. Accordingly, valinomycin promotes an autophagic cell death mode, but not apoptosis.
Authors:
Barbara Klein; Katrin Wörndl; Ursula Lütz-Meindl; Hubert H Kerschbaum
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-8-30
Journal Detail:
Title:  Apoptosis : an international journal on programmed cell death     Volume:  -     ISSN:  1573-675X     ISO Abbreviation:  -     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-8-30     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9712129     Medline TA:  Apoptosis     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Cell Biology, University of Salzburg, Hellbrunnerstr. 34, 5020, Salzburg, Austria.
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