Correspondence to: Dr Ulf T. Brunk, Division of Pathology II, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden higher doses locks the cell cycle in G0, while even more of such stress induces apoptosis. Finally, overwhelming oxidative stress will lead to necrosis. 15 That a single graduated insult may have such diverse consequences is remarkable. Why should oxidative stress above a certain magnitude no longer lead to caspase activation and apoptosis but, rather, to necrosis and uncontrolled cell death?

To further confuse the situation, agonists which induce typical apoptosis in normal cells still may kill, although in an unorthodox fashion, cells in which caspases are irreversibly inhibited or even knocked-out. 16–18 This finding of a pathway for cell death that is neither truly apoptotic nor necrotic suggests that archetypal apoptosis may require not only the participation of caspases but also of other degradative enzymes, possibly acting in concert with the caspases. These non-caspase degradative enzymes may be, of themselves, sufficient to cause unorthodox cell death, neither necrotic nor apoptotic. As described above, death domains, caspases, and mitochondria have been the major focus of research on apoptosis for quite a while. However, other cellular components also might deserve attention. During the last few years scattered reports have raised the heretical concept that lysosomes might be involved not only in necrosis, as they are well known to be, but in apoptosis as well. Although some proponents of this concept have already been burned at the stake, others are still secretly exploring it. The acidic vacuolar apparatus is the main compartment for intracellular degradation; most long-lived proteins, and all organelles, are turned-over intralysosomally19 as are phagocytosed apoptotic bodies themselves. 7, 9 There might be reasons also to link lysosomes directly to the initiation of apoptosis. These organelles contain a host of lytic enzymes with pH optima between 4.5 and 6.5, and their release from the acidic vacuolar compartment would jeopardize cellular integrity. This concept was first suggested by de Duve who nicknamed lysosomes ‘suicide bags’ not long after his discovery of these organelles in the late 1960s. 20 Between the late 1970s and early 1990s, a few studies appeared linking lysosomal rupture to cell death of the necrotic type, but apoptosis was only occasionally discussed and the general opinion, which perhaps still prevails, was that lysosomes are sturdy organelles that do not break until the cell is already in the process of dying. The latter assumption rests on observations that lysosomes, even in severely damaged cells, look surprisingly intact ultrastructurally and, thus, a number of accomplished electron microscopists have declared them normal. It has, however, long been known that lysosomes having completely normal morphology may have lost at least part of their lytic enzymes. 21