Mitochondrial permeability transition is a central coordinating event of apoptosis.

Abstract

SummaryIn 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 (Aqtm). This A~ 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 ofapoptosis. 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 A~,n disruption, BA prevents a number of phenomena linked to apoptosis: depletion ofnonoxidized glutathione, generation of reactive oxygen species, translocation of NFKB, 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 Aqr,, 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.

Mitochondrion-mediated apoptosis induced by Rana grylio virus infection in fish cells

“…Mitochondria have been suggested as the central control point of apoptosis [30]. Changes in Dwm are considered as an important event in the effect phase of apoptosis induced by many apoptotic stimuli, including virus infection [31]. Even if it is accompanied by Dwm increases at its early stage, apoptosis finally results in a Dwm collapse [32].…”

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

“…20,21 To examine the changes in MMP after SK228 treatment, MMP was measured by FACScan flow cytometer. As shown in Figure 3b, the MMP decreased dose-dependently after treatment with SK228 and the decrease of MMP started 1 hr after treatment and was sustained up to 8 hr.…”

Methods for the assessment of mitochondrial membrane permeabilization in apoptosis

“…This has been particularly substantiated by pharmacological and genetic manipulations of the IM-associated matrix protein cyclophilin D (CypD), and of the IM transmembrane protein adenine nucleotide translocase (ANT) [33][34][35]. Indeed, pharmacological inhibitors of these proteins (cyclosporin A for CypD and bongkrekic acid for ANT) are able to prevent cell death, at least in some models of apoptosis (in vitro and in vivo) [5,36]. Interestingly, the viral protein R (Vpr) from human immunodeficiency virus type I (HIV-1) exerts cytotoxic effects by promoting MMP via direct interaction with ANT (as assessed ex vivo, in purified mitochondria and artificial membranes containing ANT) [37][38][39].…”