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

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