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6th ESACP Congress, Heidelberg, April 7-11, 1999 |
A112
Both physiological cell death (apoptosis) and at least some cases of
accidental cell death involve a two-step-process. At the first level,
numerous physiological or pathological stimuli can trigger mitochondrial
permeability transition which constitutes a ratelimiting event and initiates
the common phase of the death process.
Mitochondrial permeability transition (PT) involves the formation of
proteaceous, regulated pore, probably by apposition of inner and outer
mitochondrial membrane proteins which cooperate to form the PT pore complex
(reconstituted into liposomes).
Inhibition of the PT by pharmacological intervention on mitochondrial
structures or mitochondrial expression of the apoptosisinhibitory oncoprotein
Bcl-2 thus can prevent cell death (all the steps are followed by flow
cytometric analysis). At a second level, the consequences of mitochondrial
dysfunction (studied on isolated mitochondria or in a cell-free system) can
entail a bioenergetic catastrophy and/or the activation and action of
apoptogenic proteases with secondary endonuclease activation and consequent
oligonucleosomal DNA fragmentation (apoptosis).
The acquisition of the biochemical and ultrastructural features of apoptosis
relies on the liberation of apoptogenic proteins (AIF) or protease activators
(cytochrome c) from the inter membrane space.
The notion that the mitochondrial events control cell death has major
implications for the developpement of death-inhibitory drugs. In conclusion,
AIF provides a new molecular link between mitochondrial membrane
permeabilization and nuclear apoptosis, and that the caspases, DFF/CAD and
AIF are probably engaged in complementary cooperative or redundant pathways
that lead to nuclear apoptosis.
WANDERING IN APOPTOSIS WITH FLOW CYTOMETRY:
FROM CELL TO MITOCHONDRIA.
Petit PX
INSERM U129, ICGM, Paris, France