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Tributyltin interacts with mitochondria and induces cytochrome c release
A Nishikimi1, Y Kira, E Kasahara
1Department of Biochemistry and Molecular Pathology, Osaka City University Medical School, Osaka 545-8585, Japan.
The Biochemical Journal
|May 23, 2001
Summary
Tributyltin, a triorganotin compound, induces apoptosis by disrupting mitochondrial function. It targets the adenine nucleotide translocator, opening the mitochondrial permeability transition pore and releasing cytochrome c, leading to cell death.
Area of Science:
- Biochemistry
- Cell Biology
- Toxicology
Background:
- Triorganotins are known inducers of apoptosis.
- The precise mechanisms and targets of triorganotin-induced cell death are not fully understood.
- Apoptosis can occur via cytokine-mediated or mitochondrion-dependent pathways.
Purpose of the Study:
- To investigate the effects of tributyltin on mitochondrial function.
- To elucidate the mechanism of triorganotin-induced apoptosis.
Main Methods:
- Studied the impact of tributyltin on mitochondrial membrane potential and cytochrome c release.
- Utilized inhibitors like cyclosporine A, bongkrekic acid, and dithiols (dithiothreitol, 2,3-dimercaptopropanol).
- Employed phenylarsine oxide agarose to identify molecular interactions.
Main Results:
- Low doses of tributyltin decreased mitochondrial membrane potential and induced cytochrome c release.
- These effects were inhibited by cyclosporine A, bongkrekic acid, and dithiols, but not monothiols.
- Tributyltin was found to interact with the adenine nucleotide translocator, a component of the mitochondrial permeability transition pore.
Conclusions:
- Tributyltin selectively interacts with thiol residues in the adenine nucleotide translocator at low doses.
- This interaction leads to the opening of the mitochondrial permeability transition pore.
- The opening of the pore results in decreased membrane potential and cytochrome c release, consistent with apoptosis induction.