Tributyltin interacts with mitochondria and induces cytochrome c release

Abstract

Although triorganotins are potent inducers of apoptosis in various cell types, the critical targets of these compounds and the mechanisms by which they 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 mediator and the other is by a mitochondrion-dependent mechanism. To elucidate the mechanism of triorganotin-induced apoptosis, we studied the effect of tributyltin on mitochondrial function. We found that moderately low doses of tributyltin decrease mitochondrial membrane potential and induce cytochrome c release by a mechanism inhibited by cyclosporine A and bongkrekic acid. Tributyltin-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 the adenine nucleotide translocator, a functional constituent of the mitochondrial permeability transition pore, which is selectively inhibited by dithiothreitol. These results suggest that, at low doses, tributyltin interacts selectively with critical thiol residues in the adenine nucleotide translocator and opens the permeability transition pore, thereby decreasing membrane potential and releasing cytochrome c from mitochondria, a series of events consistent with established mechanistic models of apoptosis.

Structure, Dynamics, and Membrane Topology of Stannin: A Mediator of Neuronal Cell Apoptosis Induced by Trimethyltin Chloride

“…Our structural studies reveal that the two conserved cysteine residues (Cys32 and Cys34) that constitute the putative TMT-binding site 20,21 reside at the end of the transmembrane domain close to the lipid/solvent interface, which makes these residues accessible for TMT interaction. Previous studies have shown that dialkyltin and trialkyltin compounds interact with vicinal thiol groups, resulting in cellular apoptosis, 5,74,75 lending support to the hypothesis that a direct binding of TMT may be responsible for initiating the apoptotic cascade.…”

Biological activity studies on organotin(IV)n+ complexes and parent compounds

“…Recent studies have shown that cysteine and histidine residues are the primary biological ligands for organotin(IV) compounds [85] and that vicinal dithiols rather than monothiols constitute a general target for organotin(IV) [86].…”

Biological chemistry of organotin compounds: Interactions and dealkylation by dithiols

“…One mechanism postulated for protein-organotin interactions is the formation of covalent bonds between the tin(IV) atom and thiols present in proteins [2,17,25]. This mechanism has been corroborated by recent in vitro studies showing that vicinal dithiols rather than monothiols are responsible for mediating the biochemical effects of organotin compounds [25][26][27][28].…”

“…More importantly, vicinal cysteine residues have been implicated in the progressive dealkylation of organotin compounds in both bacteria and mammals [13,28,47,48], with a mechanism similar to the degradation of alkyllead and alkylmercury compounds [49,50]. In particular, the organotin dealkylation carried out by the dithiols of SNN-PEP shows similarities to the degradation of organomercurials into inorganic Hg(II) by organomercurial lyase (MerB) in bacteria resistant to organomercurial compounds [51][52][53][54].…”

“…Moreover, alkyltin compounds have a marked preference for vicinal thiols rather than monothiols. In particular, it has been shown that both tri-and dialkyltin compounds target dithiols present in mitochondrial proteins, inducing cellular apoptosis [28,37].…”