Tributyltin interacts with mitochondria and induces cytochrome c release

Although triorganotins are potent inducers of apoptosis in various cell typ es, the critical targets of these compounds and the mechanisms by which the y lead to cell death remain to be elucidated. There are two major pathways by which apoptotic cell death occurs: one is triggered by a cytokine mediat or and the other is by a mitochondrion-dependent mechanism. To elucidate th e mechanism of triorganotin-induced apoptosis, we studied the effect of tri butyltin on mitochondrial function. We found that moderately low doses of t ributyltin decrease mitochondrial membrane potential and induce cytochrome c release by a mechanism inhibited by cyclosporine A and bongkrekic acid. T ributyltin-induced cytochrome c release is also prevented by dithiols such as dithiothreitol and 2,3-dimercaptopropanol but not by monothiols such as GSH, N-acetyl-L-cysteine, L-cysteine and 2-mercaptoethanol. Further studies with phenylarsine oxide agarose revealed that tributyltin interacts with t he adenine nucleotide translocator, a functional constituent of the mitocho ndrial permeability transition pore, which is selectively inhibited by dith iothreitol. These results suggest that, at low doses, tributyltin interacts selectively with critical thiol residues in the adenine nucleotide translo cator and opens the permeability transition pore, thereby decreasing membra ne potential and releasing cytochrome c from mitochondria, a series of even ts consistent with established mechanistic models of apoptosis.