Inhibitors of permeability transition interfere with the disruption of the mitochondrial transmembrane potential during apoptosis

AbstractIn a number of experimental systems, the early stage of the apoptotic process, i.e. the stage which precedes nuclear disintegration, is characterized by the breakdown of the inner mitochondrial transmembrane potential (ΔΨm). Here we address the question as to whether mitochondrial permeability transition (PT) pores may account for the ΔΨm dissipation in lymphocyte apoptosis. Drugs known for their PT-inhibitory potential (bongkrekic acid, cyclosporin A, and the non-immunosuppressive cyclosporin A analogue N-methyl-Val-4-cyclosporin A) are capable of preventing the apoptotic ΔΨm disruption. Moreover, pharmacological modulation of PT-mediated ΔΨm dissipation can prevent apoptosis. Thus, while suppressing the ΔΨm disruption, bongkrekic acid also inhibits the apoptotic chromatinolysis. In conclusion, these data are compatible with the hypothesis that apoptotic ΔΨm disruption is mediated by the formation of PT pores and that PT-mediated ΔΨm disruption is a critical event of the apoptotic cascade