Endoplasmic reticulum localized Bcl-2 prevents apoptosis when redistribution of cytochrome c is a late event

The disruption of mitochondrial function is a key component of apoptosis in most cell types. Localization of Bcl-2 to the outer mitochondrial and endoplasmic reticulum membranes is consistent with a role in the inhibition of many forms of apoptosis, In Rat-1 cells, a Bcl-2 mutant targeted exclusively to the endoplasmic reticulum (Bcl-cb5) was effective at inhibiting apoptosis induced by serum starvation/myc, or ceramide but not apoptosis induced by etoposide, The former conditions cause a decrease in mitochondrial transmembrane potential (Delta psi (m)) as an early event that precedes the release of cytochrome c from mitochondria, By contrast, when cells are exposed to etoposide, a situation in which cytochrome c release and membrane localization of the pro-apoptotic protein Bax precede loss of Delta psi (m), wild type Bcl-2 but not Bcl-cb5 prevents apoptosis, Therefore, Bcl-2 functions in spatially distinct pathways of apoptosis distinguished by the order of cytochrome c release and loss of Delta psi (m).