Arsenite Induces Apoptosis via a Direct Effect on the Mitochondrial Permeability Transition Pore

doi:10.1006/excr.1999.4519

Experimental Cell Research

Volume 249, Issue 2, 15 June 1999, Pages 413-421

https://doi.org/10.1006/excr.1999.4519 Get rights and content

Abstract

The molecular mode of action of arsenic, a therapeutic agent employed in the treatment of acute promyelocytic leukemia, has been elusive. Here we provide evidence that arsenic compounds may act on mitochondria to induce apoptosis. Arsenite induces apoptosis accompanied by a loss of the mitochondrial transmembrane potential (ΔΨ_m). Inhibition of caspases prevents the arsenite-induced nuclear DNA loss, but has no effect on the ΔΨ_m dissipation and cytolysis induced by arsenite. In contrast, Bcl-2 expression induced by gene transfer prevents all hallmarks of arsenite-induced cell death, including the ΔΨ_m collapse. PK11195, a ligand of the mitochondrial benzodiazepine receptor, neutralizes this Bcl-2 effect. Mitochondria are required in a cell-free system to mediate arsenite-induced nuclear apoptosis. Arsenite causes the release of an apoptosis-inducing factor (AIF) from the mitochondrial intermembrane space. This effect is prevented by the permeability transition (PT) pore inhibitor cyclosporin A, as well as by Bcl-2, which is known to function as an endogenous PT pore antagonist. Arsenite also opens the purified, reconstituted PT pore in vitro in a cyclosporin A- and Bcl-2-inhibitible fashion. Altogether these data suggest that arsenite can induce apoptosis via a direct effect on the mitochondrial PT pore.

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¹: To whom correspondence and reprint requests should be addressed at 19 rue Guy Môquet, B.P. 8, F-94801 Villejuif, France. Fax: 33-1-49 58 35 09. E-mail: [email protected].

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Rapid CommunicationArsenite Induces Apoptosis via a Direct Effect on the Mitochondrial Permeability Transition Pore

Abstract

Blood

Blood

Blood

Blood

Blood

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Exp. Cell Res.

Exp. Cell Res.

Trends Cell Biol.

Trends Biochem. Sci.

Enzymatic methylation of arsenic species and other new approaches to arsenic toxicity

Annu. Rev. Pharmacol. Toxicol.

Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide

New Engl. J. Med.

The induction of apoptosis and cell cycle arrest by arsenic trioxide in lymphoid neoplasms

Leukemia

Arsenic induces apoptosis in B-cell leukaemic cell lines in vitro: Activation of caspases and down-regulation of Bcl-2 protein

Br. J. Haematol.

Teratogen-induced cell death in postimplantation mouse embryos: Differential tissue sensitivity and hallmarks of apoptosis

Cell Death Differ.

Involvement of reactive oxygen species and caspase 3 activation in arsenite-induced apoptosis

J. Cell. Physiol.

Arsenite blocks growth factor induced activation of the MAP kinase cascade, upstream of Ras and downstream of GrB2-Sos

Oncogene

PML induces a novel caspase-independent death process

Nat. Gen.

The biochemistry of apoptosis

FASEB J.

The permeability transition pore complex: A target for apoptosis regulation by caspases and Bcl-2 related proteins

J. Exp. Med.

Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis

Science

Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria

Proc. Natl. Acad. Sci. USA

Mitochondrial control of nuclear apoptosis

J. Exp. Med.

The proto-oncogene Bcl-2 and its role in regulating apoptosis

Nature Med.

Rapid Communication
Arsenite Induces Apoptosis via a Direct Effect on the Mitochondrial Permeability Transition Pore