Ancient Romans knew it: the best way to take control over an enemy during a battle was to divide its army. Recent data suggest that during apoptosis mitochondria may be condemned to the role of Romans’ enemies, being divided to become defeated. Mitochondrial defeat is represented by the release of several proteins, needed in the cytosol to activate the effector caspases. 1 Among the released proteins, cytochrome c, the only soluble component of the respiratory chain, is an essential cofactor for the formation of the so-called apoptosome with the subsequent activation of caspase-9. The mechanism by which cytochrome c is released is heavily investigated and debated. Molecules of the BCL-2 family have a prominent role in the control of this process: proapoptotic BCL-2 members promote the release of cytochrome c, whereas the antiapoptotic ones prevent it. 2 BCL-2 family proteins are characterized by homology in short amphipathic stretches of amino acids, called BCL-2 homology (BH) domains. Antiapoptotic members display sequence conservation throughout all four BH domains. Proapoptotic BCL-2 members can be further subdivided into ‘multidomain’members possessing homology in BH1-3 domains (such as BAX and BAK) and ‘BH3-only’members that display only B9 amino acids of homology within this domain. 3 In a widely accepted model, the BH3-only molecules connect upstream signals to the mitochondrial pathway: for example, BID recruits the mitochondria during death receptor-induced apoptosis4 and BIM is essential for T cell receptor-induced apoptosis. 5 Once activated, BH3-only proteins function as ligands for the multidomain proapoptotics BAX and BAK, induce their homo/hetero-oligomerization and ultimately the release of cytochrome c from mitochondria. 6 Several different and sometimes mutually exclusive mechanisms have been proposed to explain the mitochondrial events that lead to the efflux of cytochrome c (see Martinou and Green7 for a review), often generating more confusion than knowledge. Mitochondrial structural organization further complicates this already bamboozled scenario. The classic textbook depiction of mitochondria as individual, isolated organelles with an outer membrane that separates them from the cytosol and an inner membrane invaginated in large baffles, the cristae, that freely communicate with the intermembrane space, is probably oversimplified. High-voltage electron tomography coupled with three-dimension image reconstruction of mitochondria depicted a more complex internal structure. The cristae constitute a separate compartment, shaped like bags and connected by narrow tubular junctions to a thin intermembrane space. 8 In situ, mitochondria appear to be organized in a net, where individual organelles dynamically fuse and divide. 9 Moreover, this mitochondrial reticulum is in close proximity with the endoplasmic reticulum (ER), often closer than the discrimination capabilities of highresolution confocal microscopy. 10 This structural organization influences multiple parameters of mitochondrial physiology during life and death of the cell. The narrow tubular junctions generate gradients of ions and small molecules along the cristae and are responsible for the segregation of cytochrome c in the cristae compartment, 11 where the majority of the respiratory chain complexes also localize. 12–14 Mitochondrial fusion in situ is efficient15 and fused mitochondria can behave as a functional unit, where a stimulus or a signal hitting one end of the mitochondrial wire is readily transmitted to other distal components of the net. 16 This property can be extremely useful to convey signals across the …