Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore.
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 (Delta Psim). Inhibition of caspases prevents the arsenite-induced nuclear DNA loss, but has no effect on the Delta Psim 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 Delta Psim 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.
Larochette
N
N
Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, 19 rue Guy Môquet, Villejuif, F-94801, France.
Decaudin
D
D
Jacotot
E
E
Brenner
C
C
Marzo
I
I
Susin
S A
SA
Zamzami
N
N
Xie
Z
Z
Reed
J
J
Kroemer
G
G
D017209:Apoptosis / Q000187:drug effects*; D001152:Arsenicals / Q000494:pharmacology; D018053:Arsenites / Q000494:pharmacology*; D061945:Caspase Inhibitors; D005434:Flow Cytometry; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D020298:U937 Cells
D001152:Arsenicals; D018053:Arsenites; D061945:Caspase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; C029341:oxophenylarsine