Mitochondrial permeability transition is a central coordinating event of apoptosis.

TLDR

The early apoptotic stage is marked by loss of mitochondrial inner membrane potential due to opening of permeability transition pores, a Bcl‑2‑regulated event that can trigger chromatinolysis in cell‑free systems. The study investigates which downstream apoptotic events depend on mitochondrial permeability transition. The authors examined the effect of the PT inhibitor bongkrekic acid on glucocorticoid‑induced thymocyte apoptosis. Bongkrekic acid blocks Δψm loss and prevents glutathione depletion, ROS generation, NF‑κB translocation, phosphatidylserine exposure, vacuolization, chromatin condensation, DNA fragmentation, and p53‑dependent apoptosis, indicating that many apoptotic phenotypes are secondary to PT and that Δψm disruption follows transcriptional signals, positioning PT upstream of nuclear and membrane death features.

Abstract

In a number of experimental systems, the early stage of the apoptotic process, i.e., the stage that precedes nuclear disintegration, is characterized by the breakdown of the inner mitochondrial transmembrane potential (delta psi m). This delta psi m disruption is mediated by the opening of permeability transition (PT) pores and appears to be critical for the apoptotic cascade, since it is directly regulated by Bcl-2 and since mitochondria induced to undergo PT in vitro become capable of inducing nuclear chromatinolysis in a cell-free system of apoptosis. Here, we addressed the question of which apoptotic events are secondary to mitochondrial PT. We tested the effect of a specific inhibitor of PT, bongkrekic acid (BA), a ligand of the mitochondrial adenine nucleotide translocator, on a prototypic model of apoptosis glucocorticoid-induced thymocyte death. In addition to abolishing the apoptotic delta psi m disruption, BA prevents a number of phenomena linked to apoptosis: depletion of nonoxidized glutathione, generation of reactive oxygen species, translocation of NF kappa B, exposure of phosphatidylserine residues on the outer plasma membrane, cytoplasmic vacuolization, chromatin condensation, and oligonucleosomal DNA fragmentation. BA is also an efficient inhibitor of p53-dependent thymocyte apoptosis induced by DNA damage. These data suggest that a number of apoptotic phenomena are secondary to PT. In addition, we present data indicating that apoptotic delta psi m disruption is secondary to transcriptional events. These data connect the PT control point to the p53- and ICE/ Ced 3-regulated control points of apoptosis and place PT upstream of nuclear and plasma membrane features of PCD.