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Mitochondria in Apoptosis
Increases in cytosolic Ca2+ levels due to activation of ion channel-linked receptors, such as that for the excitatory amino acid neurotransmitter glutamic acid, can induce permeability transition (PT) of the mitochondrial membrane. PT constitutes the first rate-limiting event of the common pathway of apoptosis. Upon PT, apoptogenic factors leak into the cytoplasm from the mitochondrial intermembrane space. Two such factors, cytochrome c and apoptosis inducing factor (AIF), begin a cascade of proteolytic activity that ultimately leads to nuclear damage (DNA fragmentation, DNA mutations) and cell death. Cytochrome C, a key protein in electron transport, appears to act by forming a multimeric complex with Apaf-1, a protease, which in turn activates procaspase 9, and begins a cascade of activation of downstream caspases. Smac/Diablo is released from the mitochondria and inhibits IAP (inhibitor of apoptosis) from interacting with caspase 9 leading to apoptosis. Bcl-2 and Bcl-X can prevent pore formation and block the release of cytochrome c from the mitochondria and prevent activation of the caspase cascade and apoptosis. PT is also related to the mitochondrial generation of reactive oxygen species which plays a role in the degradation phase of apoptosis (i.e. plasma membrane alterations).
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References:
Budihardjo, I., et al., Biochemical pathways of caspase activation during apoptosis. Annu. Rev. Cell Dev. Biol., 15, 269-290 (1999).
Susin, S.A., et al., Molecular characterization of mitochondrial apoptosis-inducing factor. Nature, 397, 441-446 (1999).
Cai, J., et al., Mitochondrial control of apoptosis: the role of cytochrome c. Biochim. Biophys. Acta, 1366, 139-149 (1998).
Lee, H., and Wei, Y., Mitochondrial role in life and death of the cell. J. Biomed. Sci., 7, 2-15 (2000).
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