Why are mitochondria involved in apoptosis? Permeability transition pores and apoptosis as selective mechanisms to eliminate superoxide-producing mitochondria and cell

Petit and co-authors have recently summarized results of their studies on the involvement of mitochondria in apoptosis [Petit et al. (1996) FEBS Lett. 396, 7-13]. The mechanism consists in the release to the cytosol of a protein (presumably a protease) that is normally sequestered in the intermembrane space of mitochondria. This protein, when added to isolated nuclei, caused typical apoptotic changes. Its release from mitochondria was shown to occur as a result of disruption of the outer mitochondrial membrane due to smelling of mitochondria caused by opening of so-called permeability transition pores in their inner membranes. Increase in the level of products of the one-electron reduction of O-2 (reactive oxygen species, ROS) is known to induce the mitochondrial pores. The hypothesis described here assumes that pore formation and apoptosis are involved in the organization of a defense system preventing ROS formation. It is proposed that ROS-induced pore opening lowers ROS production due to (a) maximal stimulation of mitochondrial O-2 consumption and, hence, intracellular [O-2] lowering and (b) complete dissipation of mitochondrial membrane potentials and, as a consequence, maximal oxidation of such respiratory chain carriers as CoQ(.-) which serve as one-electron O-2 reductants. ROS decrease allows pore closure. If, nevertheless, ROS are still accumulating in a mitochondrion, long-lived pores cause degradation of the organelle which cannot import and synthesize proteins due to the absence of the membrane potential. In this way, ROS-producing mitochondria can be eliminated (mitochondrial selection). Another result of the long-lived pores is mitochondrial swelling. This disrupts the outer mitochondrial membrane and releases the apoptosis-inducing protein. Apoptosis eliminates ROS-producing cells (cell selection).