The permeability transition pore signals apoptosis by directing Bax translocation and multimerization.
FASEB j.. 2002-02-25; 16(6): 607-609
DOI: 10.1096/fj.01-0269fje
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Mitochondria are key players of apoptosis and can irreversibly commit the cell to
death by releasing cytochrome c (Cyt.c) to the cytosol, where caspases 9 and 3
subsequently get activated. Under conditions of oxidative stress, opening of the
mitochondrial permeability transition pore (PTP) represents an early trigger and
is crucial in causing Cyt.c release. To account for the latter, current models
propose that PTP gating would result, as is the case in vitro, in the rupture of
the outer mitochondrial membrane caused by mitochondrial matrix swelling. Using
live cell imaging and recombinant fluorescent probes based on the green
fluorescent protein (GFP) and its mutants, we report that directed repetitive
gating of the PTP triggers a delayed Cyt.c efflux, which is not associated with
mitochondrial swelling. Instead, subcellular imaging shows that PTP opening
signals the redistribution of the cytosolic protein Bax to the mitochondria,
where it secondarily forms clusters that appear to be a prerequisite for Cyt.c
release. Fluorescence resonance energy transfer imaging further reveals that Bax
clustering coincides with the formation of Bax multimers. We conclude that the
PTP is not itself a component of the Cyt.c release machinery, but that it acts
indirectly by signaling Bax translocation and multimerization.