Mitochondria in Apoptosis

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Mitochondria in Apoptosis
SIGMA-ALDRICH
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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). References Bu
dihardjo, 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).