The Permeability Transition and BCL-2 Family Proteins in Apoptosis: Co-conspirators or Independent Agents?

Programmed cell death (PCD), or apoptosis, is part of the normal biology of all metazoan organism and, when inappropriately activated or inhibited, has been implicated in a variety of human diseases. Cell death pathways critically depend on the participation of mitochondria; indeed, mitochondria play a pivotal role in cell survival and tissue development not only by virtue of their role in apoptosis but also due to their key function in energy production. These roles of mitochondria center, in part, around their participation in the dynamic processes by which cellular levels of Ca2+ are modulated. In this context, mitochondria are critical contributors to the regulation of cellular Ca2+ levels, accumulating cytoplasmic Ca2+ whenever the local cytoplasmic free Ca2+ rises above a critical ‘set point’ and slowly releasing Ca2+ when cytoplasmic Ca2+ is lowered below this set point. In addition, the close coupling of mitochondrial and ER Ca2+ levels has defined an interaction that is tightly and subtly organized, and coordinated on a subcellular basis, so that spatial and temporal details of the Ca2+ signal may be defined by the spatial organization and possibly specialization of mitochondrial populations within cells.