Mitochondria play a central role in maintaining cells alive, but are also important mediators of cell death. The main event in mitochondrial signalling and control of apoptosis is the permeabilisation of the outer mitochondrial membrane and the release of pro-apoptotic proteins into the cytosol from the mitochondrial intermembrane space. With respect to death receptor-mediated apoptosis, the activation of the mitochondrial pathway is required for apoptosis induction in cells which are described as "type II" cells whereas "type I" cells do not require it. In type I cells, activation of the extrinsic pathway is sufficient to induce apoptosis. This review deals with the events that enable cell death in type II cells, i.e., the signals that lead from death receptor stimulation to permeabilisation of the outer mitochondrial membrane. Caspase-8 and Bid are the known procurers of the death signal in this part of the apoptotic pathway. Currently many exciting new findings are emerging concerning the regulation of caspase-8 and Bid function and activation. We will take you on a journey through these new developments and point out what we consider the major unknowns in this field. We end our review on an up-to-date discussion of the determinants of the type I-type II cell distinction. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.
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