Overview scheme depicting the proposed requirement of the ER and mitochondria in TNF-R1/ceramide-mediated ciPCD. Known proximal mediators of TNF-R1/ceramide-induced ciPCD are indicated, as are mediators of ciPCD that potentially act downstream of the ER and mitochondria. Only wildtype Bcl-2 simultaneously acting at the ER, at mitochondria and at the nucleus efficiently blocks the caspase-independent death signals of TNF-R1/ceramide, whereas Bcl-2 constructs specifically localizing to each organelle do not prevent ciPCD. This suggests that the corresponding signaling pathways of TNF-R1/ceramide target both the ER and mitochondria, and that both organelles participate in ciPCD via a molecular crosstalk. The nucleus may represent a further organelle that participates in these signaling pathways, yet its role remains to be confirmed.