An intracellular wave of cytochrome c propagates and precedes Bax redistribution during apoptosis

L. Lartigue, C. Medina, L. Schembri, P. Chabert, M. Zanese, F. Tomasello, R. Dalibart, D. Thoraval, M. Crouzet, F. Ichas, F. De Giorgi
Journal of Cell Science. 2008-10-07; 121(21): 3515-3523
DOI: 10.1242/jcs.029587

PubMed
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Bax is considered to be pivotal in inducing cytochrome c release (CCR) from
mitochondria during apoptosis. Indeed, Bax redistributes to the mitochondrial
outer membrane (MOM) upon activation and forms homo-multimers that are capable of
permeabilizing the MOM. Our attempts to image this sequence of events in single
live cells resulted in unexpected observations. Bax redistribution exhibited two
distinct components: an early minor redistribution that was silent in terms of
homo-multimerization and a major late redistribution that was synchronous with
the formation of Bax multimers, but that proceeded belatedly, i.e. only after
caspase 3/7 (C3/7) had already been activated. Intriguingly, neither of these two
components of redistribution correlated with CCR, which turned out to be
spatially organized, propagating as a traveling wave at constant velocity.
Strikingly, propagation of the CCR wave (1) preceded signs of in situ Bax
conformational activation; (2) appeared to be independent of autocatalytic loops
involving a positive feedback of either C3/7, Ca(2+) mobilization or
mitochondrial permeability transition; and (3) was triggered by diffuse
stimulation with the synthetic Bak activator BH3I-1 but then proceeded
independently of Bak activation. Thus, the CCR wave not only questions the exact
role of Bax redistribution in cell death, but also indicates the existence of yet
unidentified positive-feedback loops that ensure a spatiotemporal control of
apoptosis at the subcellular scale.

 

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