Tributyltin-induced apoptosis requires glycolytic adenosine trisphosphate production.
The toxicity of tributyltin chloride (TBT) involves Ca(2+) overload, cytoskeletal damage, and mitochondrial failure leading to cell death by apoptosis or necrosis. Here, we examined whether the intracellular ATP level modulates the mode of cell death after exposure to TBT. When Jurkat cells were energized by the mitochondrial substrate, pyruvate, low concentrations of TBT (1-2 microM) triggered an immediate depletion of intracellular ATP followed by necrotic death. When ATP levels were maintained by the addition of glucose, the mode of cell death was typically apoptotic. Glycolytic ATP production was required for apoptosis at two distinct steps. First, maintenance of adequate ATP levels accelerated the decrease of mitochondrial membrane potential, and the release of the intermembrane proteins adenylate kinase and cytochrome c from mitochondria. A possible role of the adenine nucleotide exchanger in this first ATP-dependent step is suggested by experiments performed with the specific inhibitor, bongkrekic acid. This substance delayed cytochrome c release in a manner similar to that caused by ATP depletion. Second, caspase activation following cytochrome c release was only observed in ATP-containing cells. Bcl-2 had only a minor effect on TBT-triggered caspase activation or cell death. We conclude that intracellular ATP concentrations control the mode of cell death in TBT-treated Jurkat cells at both the mitochondrial and caspase activation levels.
Stridh
H
H
Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, S-171 77 Stockholm, Sweden.
Fava
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E
Single
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B
Nicotera
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P
Orrenius
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S
Leist
M
M
D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D017209:Apoptosis / Q000187:drug effects*; D001865:Bongkrekic Acid / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D014220:Trialkyltin Compounds / Q000494:pharmacology*
D003574:Cytochrome c Group; D011506:Proteins; D014220:Trialkyltin Compounds; D001865:Bongkrekic Acid; C011559:tributyltin; D000255:Adenosine Triphosphate; D020169:Caspases