THE CENTRAL ROLE OF THE MITOCHONDRIAL MEGACHANNEL IN APOPTOSIS - EVIDENCE OBTAINED WITH INTACT-CELLS, ISOLATED-MITOCHONDRIA, AND PURIFIED PROTEIN COMPLEXES

The mitochondrial megachannel (also called permeability transition por e) is a polyprotein complex formed in the contact site between the inn er and the outer mitochondrial membranes and participates in the regul ation of mitochondrial membrane permeability. We have obtained three i ndependent lines of evidence suggesting the implication of the mitocho ndrial megachannel in apoptosis. First, in intact cells, apoptosis is accompanied by an early dissipation of the mitochondrial transmembrane potential (Delta Psi(m)). In several models of apoptosis, specific ag ents inhibiting the mitochondrial megachannels prevent this Delta Psi( m) dissipation and simultaneously abolish the manifestations of caspas e- and endonuclease activation, indicating that megachannel opening is a critical event of the apoptotic process. Second, mitochondria are r ate-limiting far caspase and nuclease activation in several cell-free systems of apoptosis. Isolated mitochondria release apoptogenic factor s capable of activating pro-caspases or endonucleases upon opening of the mitochondrial megachannel in vitro. Third, opening of the purified megachannel reconstituted into Liposomes is inhibited by recombinant Bcl-2 or Bcl-XL, two apoptosis-inhibitory proteins which also prevent megachannel opening in cells and isolated mitochondria. This indicates that the megachannel is under the direct regulatory control of anti-a poptotic members of the Bcl-2 family. Altogether, our results suggest that megachannel opening is sufficient and (mostly) necessary for trig gering apoptosis. (C) 1998 Elsevier, Paris.