In 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 (ΔΨ m). Here we address the question as to whether mitochondrial permeability transition (PT) pores may account for the ΔΨ m 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 ΔΨ m disruption. Moreover, pharmacological modulation of PT-mediated ΔΨ m dissipation can prevent apoptosis. Thus, while suppressing the ΔΨ m disruption, bongkrekic acid also inhibits the apoptotic chromatinolysis. In conclusion, these data are compatible with the hypothesis that apoptotic ΔΨ m disruption is mediated by the formation of PT pores and that PT-mediated ΔΨ m disruption is a critical event of the apoptotic cascade.
