The permeability transition pore signals apoptosis by directing Bax translocation and multimerization

被引:219
作者
De Giorgi, F
Lartigue, L
Bauer, MKA
Schubert, A
Grimm, S
Hanson, GT
Remington, SJ
Youle, RJ
Ichas, F [1 ]
机构
[1] Univ Bordeaux 2, European Inst Chem & Biol, INSERM, E9929, F-33076 Bordeaux, France
[2] Max Planck Inst Biochem, D-82152 Martinsried, Germany
[3] Univ Oregon, Dept Chem, Eugene, OR 97403 USA
[4] Univ Oregon, Dept Phys, Eugene, OR 97403 USA
[5] Univ Oregon, Inst Mol Biol, Eugene, OR 97403 USA
[6] NINCDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA
关键词
apoptosis; bax; cytochrome c; FRET; permeability transition pore;
D O I
10.1096/fj.01-0269fje
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:607 / +
页数:20
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