Potential mechanisms of mitochondrial cytochrome-c release during apoptosis

Cytochrome-c release from the intermembrane space of mitochondria to the cy toplasm is a critical signaling event during many forms of apoptotic cell d eath. Due to the widespread involvement of apoptosis in pathobiology, this mitochondrial event is a logical target for the development of new therapeu tic approaches to numerous diseases. Currently impeding such a development is our lack of understanding of the mechanism by which release of this comp onent of the electron transport chain occurs in response to the wide variet y of agents known to induce apoptosis. Release induced by the membrane perm eability transition (a permeability change at the inner mitochondrial membr ane) likely results from mitochondrial swelling, consequent rupture of the outer mitochondrial membrane, and nonspecific release of intermembrane spac e contents. An alternative mode of release may include the induction of a s pecific permeability change at the outer mitochondrial membrane. These two mechanisms present distinct molecular targets for drug development. (C) 199 9 Wiley-Liss, Inc.