Tributyltin-induced apoptosis requires glycolytic adenosine trisphosphate production

The toxicity of tributyltin chloride (TBT) involves Ca2+ overload, cytoskel etal damage, and mitochondrial failure leading to cell death by apoptosis o r necrosis. Here, we examined whether the intracellular ATP level modulates the mode of cell death after exposure to TBT. When Jurkat cells were energ ized by the mitochondrial substrate, pyruvate, low concentrations of TBT (1 -2 mu M) 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 ade quate ATP levels accelerated the decrease of mitochondrial membrane potenti al, and the release of the intermembrane proteins adenylate kinase and cyto chrome c from mitochondria. A possible role of the adenine nucleotide excha nger in this first ATP-dependent step is suggested by experiments performed with the specific inhibitor, bongkrekic acid. This substance delayed cytoc hrome c release in a manner similar to that-caused by ATP depletion. Second , caspase activation following cytochrome c release was only observed in AT P-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 mit ochondrial and caspase activation levels.