An intracellular wave of cytochrome c propagates and precedes Bax redistribution during apoptosis.
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.
Lartigue
Lydia
L
INSERM U916, Université Bordeaux 2, Institut Bergonié, 229 cours de l'Argonne, 33000 Bordeaux, France.
Medina
Chantal
C
Schembri
Laura
L
Chabert
Paul
P
Zanese
Marion
M
Tomasello
Flora
F
Dalibart
Renée
R
Thoraval
Didier
D
Crouzet
Marc
M
Ichas
François
F
De Giorgi
Francesca
F
D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism*; D019281:Dimerization; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D011487:Protein Conformation; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D053148:Caspase 3; D053179:Caspase 7; D002118:Calcium