Potential mechanisms of mitochondrial cytochrome‐C release during apoptosis

Abstract

Cytochrome-c release from the intermembrane space of mitochondria to the cytoplasm is a critical signaling event during many forms of apoptotic cell death. Due to the widespread involvement of apoptosis in pathobiology, this mitochondrial event is a logical target for the development of new therapeutic approaches to numerous diseases. Currently impeding such a development is our lack of understanding of the mechanism by which release of this component of the electron transport chain occurs in response to the wide variety of agents known to induce apoptosis. Release induced by the membrane permeability transition (a permeability change at the inner mitochondrial membrane) likely results from mitochondrial swelling, consequent rupture of the outer mitochondrial membrane, and nonspecific release of intermembrane space contents. An alternative mode of release may include the induction of a specific permeability change at the outer mitochondrial membrane. These two mechanisms present distinct molecular targets for drug development. Drug Dev. Res. 46:18–25, 1999. © 1999 Wiley-Liss, Inc.