Distinct stages of cytochrome c release from mitochondria: evidence for a feedback amplification loop linking caspase activation to mitochondrial dysfunction in genotoxic stress induced apoptosis

被引:230
作者
Chen, Q
Gong, B
Almasan, A
机构
[1] Cleveland Clin Fdn, Lerner Res Inst NB40, Dept Canc Biol, Cleveland, OH 44195 USA
[2] Cleveland Clin Fdn, Dept Radiat Oncol, Cleveland, OH 44195 USA
关键词
apoptosis; mitochondria; cytochrome c; caspases; ionizing radiation; Bcl-2;
D O I
10.1038/sj.cdd.4400629
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
Cytochrome c (cyto c) release from mitochondria is a critical event in apoptosis, By investigating the ordering of molecular events during genotoxic stress-induced apoptosis, we found that ionizing radiation (IR) and etoposide induced the release of cyto c from mitochondria in two distinct stages. The early release of low levels of cyto c into the cytosol preceded the activation of caspase 9 and 3, but had no eff ect on ATP levels or mitochrondrial transmembrane potential (Delta psi(m)). In contrast, the late stage cyto c release resulted in a drastic loss of mitochondrial cyto c and was associated with reduction of ATP levels and Delta psi(m). Moreover, caspases contributed to the late cyto c release since the caspase inhibitor zVAD prevented only the late but not the early-stage cyto c release. Recombinant caspase 3 induced cyto c release from isolated mitochondria in the absence of cytosolic factors. Bcl-2 but not Bid was cleaved during apoptosis after caspase activation. This suggests that Bcl-2 cleavage might contribute to the late cyto c release, which results in mitochondrial dysfunction manifested by the decrease of ATP and Delta psi(m). zVAD prevented the reduction of ATP, Delta psi(m), and nuclear condensation when added up to 8 h after IR, at the time the caspases were highly activated but when the majority of cyto c was still maintained in the mitochondria. These findings link the feedback loop control of caspase-induced cyto c release with mitochondrial dysfunction manifested by ATP and Delta psi(m) decline.
引用
收藏
页码:227 / 233
页数:7
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