When separation means death: Killing through the mitochondria, but starting from the endoplasmic reticulum

Abstract

Proteins of the BCL-2 family are key mitochondrial actors in the intrinsic pathway of apoptosis. However, they also exert housekeeping functions at the level of the endoplasmic reticulum (ER), controlling Ca2+ homeostasis and the unfolded protein response (UPR). Klee et al (2009) in an article published in this issue, identified that proapoptotic proteins of the BCL-2 family can activate the mitochondrial pathway of death also when restricted only at the ER, by engaging an atypical arm of the UPR requiring Ca2+. This paper elucidates how unconventional cascades overcome the spatial restriction of cellular signalling components and add a further layer of complexity to the regulation of cell death. © 2009 European Molecular Biology Organization.