|
In recent years, scientists have come to understand that the effectors of cell death, particularly apoptosis, are represented by a family of intracellular cystein proteases, known as caspases. A variety of key events in apoptosis focus on mitochondria suggesting that mitochondria have a pivotal part in controlling cell life and death. At least three general mechanisms are known and interrelated: |
|
- The loss of electron transport in the respiratory chain, which can be induced by G-irradiation, ceramide, ligation of Fas ... should have as consequence a drop in ATP synthesis. Indeed, ATP appears to be required for downstream events in apoptosis. Thus, although the loss of mitochondrial ATP synthesis can kill the cell, it is unlikely a mechanism for induction of apoptosis. - The release of caspase-activating-proteins such as cytochrome c (Cyt C) and AIF. The biochemical role played by these factors in apoptosis is still unclear, but some details are being revealed: Cyt C binds to Apaf 1 in the presence of ATP and caspase 9, inducing cleavage of procaspase 9 with the release of active caspase 9 that cleaves and activates procaspase 3. This one induces proteolitic cleavage of a range of target proteins responsible for the rearrangement of the cytosol, nucleus and plasma membrane that are characteristic of apoptosis. However, Cyt C and AIF leave the intermembrane space by unclear mechanisms. The most common hypothesis involves the drop of membrane potential, the formation and the opening of the Mitochondrial Permeability Transition pore (MPT) and the release of pro-apoptotic proteins such as Bad, Bax, Bid. However, it is clear that some natural anti-apoptotic proteins such as Bcl2 and Bclxl, which bind on the mitochondrial outer membrane, can participate to the regulation of MPT. - Mitochondria are the major source of superoxide anion production in the cell. The respiratory chain looses 2 to 3 % of the electrons during their transfer to molecular oxygen, most participating in the production of superoxide anion. Superoxide anion and its ROS derivatives are increased during apoptosis induced by different stimuli. However, the ROS generation seems to be a relatively late event in the apoptosis cascade. |
|
In addition to these three general mechanisms, it is interesting to underline that an increase of mitochondrial Ca2+ sequestration can also induced an inhibition of the oxidative phosphorylation, a drop of membrane potential, a MPT pore opening, a release of Cyt C and a ROS generation. Consequently, mitochondria participate to life and death decisions in the cell, regulating its main functions. |