If the life or death of the cell depends on the location of cytochrome c and its companions of doom, it's not surprising that medical research has focused on the specific mechanism that releases these molecules from the mitochondria. Again the answer is complicated, but helps clarify the link between the intrinsic and extrinsic pathways of apoptosis. Overlooking a few exceptions, likely to be refinements, these findings place the mitochondria at the centre of both forms of cell death. In almost all cases, the basic apparatus of death is controlled by the mitochondria. When enough mitochondria in a cell spill out their death proteins—probably beyond a threshold point of no return—then the cell inexorably goes on to kill itself.
The release of cytochrome c takes place in two steps, according to recent research from Sten Orrenius and his colleagues at the Karolinska Institutet in Stockholm. In the first step, the protein is mobilized from the membrane itself. Cytochrome c is normally bound loosely to lipids (especially cardiolipin) in the inner mitochondrial membrane, and is released only upon the oxidation of these lipids. This explains the requirement for free radicals in apoptosis: they oxidize the lipids in the inner membrane to release cytochrome c from its shackles. But this is still only half the story. Cytochrome c is mobilized into the inter-membrane space, and it can't escape from the mitochondria altogether until the outer membrane has become more permeable. This is because cytochrome c is a protein, and so is too large to cross the membrane in normal circumstances. If it is to escape the mitochondrion, some sort of pore must breach the outer membrane.
The nature of the pore that opens in the outer mitochondrial membrane has foxed researchers for a decade or more. It seems probable that several distinct mechanisms can operate under different circumstances, giving rise to at least two different types of pore. One mechanism apparently involves metabolic stress to the mitochondria themselves, which leads to excess free-radical generation. The rising stress opens up a pore in the outer membrane, known as the permeability transition pore, leading to swelling and rupture of the outer membrane, coupled with the release of proteins.
Another pore, which may be of more general significance, involves a large family of proteins known rather dryly as the bcl-2 family. The name is now largely irrelevant, and stands for 'B cell lymphoma/leukaemia-2', which refers to the oncogene discovered by cancer researchers in the 1980s. At least 21 related genes have since been discovered, which code for proteins in the family. These proteins fall into two broad groups, which battle among themselves in ways that are complex and still largely obscure. One group protects against apoptosis. They are found in the outer mitochondrial membrane and seem to prevent the formation of pores, thus blocking the release of proteins like cytochrome c into the cytosol. The other group are diametrically opposed: they act to form pores, apparently large enough to allow the escape of proteins from the mitochondria directly. This group thereby promotes apoptosis. They are normally found elsewhere in the cell, and migrate to the mitochondria upon receiving some sort of signal. The final outcome—whether or not the cell commits apoptosis—depends on the numerical balance of the feuding family members in the mitochondrial membrane, and the number of mitochondria embroiled in the battle. If the pro-apoptosis members outnumber their protective cousins in a sufficient number of mitochondria, the pores open, the death proteins are spilled out from the mitochondria, and the cell goes on to kill itself.
The existence of the feuding bcl-2 family helps explain the links between the two different forms of apoptosis, the intrinsic and extrinsic pathways. Many different signals alter the balance of the feud in the mitochondria, either in favour of or against apoptosis. For example, both the 'death' signals from outside the cell (the extrinsic pathway) and the 'damage' signals from inside the cell (the intrinsic pathway) alter the feuding family balance in favour of apoptosis.2 Thus the bcl-2 proteins integrate a diverse array of signals from both outside and inside the cell, and calibrate their strength in the mitochondria. If the balance favours death, pores form in the outer membrane, cytochrome c and other proteins spill out, and the caspase cascade is activated. Thus the final events are the same in most cases.
The centrality of mitochondria to both the main forms of apoptosis raises the possibility that it was ever thus. We have discussed the fact that bacteria and cancer cells act independently in their own interests, and so can be seen as 'units of selection'. At one and the same time, selection can operate at the level of the cell and that of the individual. Mitochondria were once free-living bacteria, and at that time operated independently. Once incorporated into the eukaryotic cell, they presumably retained the power to operate as independent cells, at least for a while: they were independent cells living within a larger organism, and could rebel in the same way as cancer cells (also independent cells living within a larger organism).
If, today, mitochondria bring about the demise of their host cell, might it be that from the very beginning, the mitochondria killed their host cells in their own interests? In other words, the origin of apoptosis was not an altruistic act on behalf of the individual, but a selfish act on behalf of the tenants themselves. If this view is correct, then apoptosis is better seen as murder than suicide. And if so, the reason why single cells should apparently commit suicide is clear: they are sabotaged from within. So is there any evidence that the mitochondria brought with them to the eukaryotic merger the apparatus of death? Indeed there is.
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