Multipolar functions of BCL-2 proteins link energetics to apoptosis.

Classical apoptotic cell death is now sufficiently well understood to be interrogated with mathematical modeling and manipulated with targeted drugs for clinical benefit. However, a biological black hole has emerged with the realization that apoptosis regulators are functionally multipolar. BCL-2 family proteins appear to have much greater effects on cells than can be explained by their known roles in apoptosis. Although these effects may be observable simply because the cell is not dead, the general assumption is that BCL-2 proteins have undiscovered biochemical activities. Conversely, these as yet uncharacterized day-jobs also may underlie their profound effects on cell survival, challenging current assumptions about classical apoptosis. Even their sub-mitochondrial localizations remain controversial. Here we attempt to integrate seemingly conflicting information with the prospect that BCL-2 proteins themselves may be the critical crosstalk between life and death.