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 char acterized by the breakdown of the inner mitochondrial transmembrane po tential (Delta Psi(m)). Here we address the question as to whether mit ochondrial permeability transition (PT) pores may account for the Delt a Psi(m) dissipation in lymphocyte apoptosis, Drugs known for their PT -inhibitory potential (bongkrekic acid, cyclosporin A, and the non-imm unosuppressive cyclosporin A analogue N-methyl-Val-4-cyclosporin A) ar e capable of preventing the apoptotic Delta Psi(m) disruption, Moreove r, pharmacological modulation of PT-mediated Delta Psi(m) dissipation can prevent apoptosis. Thus, while suppressing the Delta Psi(m) disrup tion, bongkrekic acid also inhibits the apoptotic chromatinolysis. In conclusion, these data are compatible with the hypothesis that apoptot ic Delta Psi(m) disruption is mediated by the formation of PT pores an d that PT-mediated Delta Psi(m) disruption is a critical event of the apoptotic cascade.