Endoplasmic reticulum BIK initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis

被引:279
作者
Germain, M
Mathai, JP
McBride, HM
Shore, GC
机构
[1] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada
[2] Univ Ottawa, Inst Heart, Ottawa, ON, Canada
[3] McGill Univ, McGill Canc Ctr, Montreal, PQ H3G 1Y6, Canada
关键词
Bax; calcium; caspase; fission; NOXA;
D O I
10.1038/sj.emboj.7600592
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
The endoplasmic reticulum ( ER) can elicit proapoptotic signalling that results in transmission of Ca2+ to the mitochondria, which in turn stimulates recruitment of the fission enzyme DRP1 to the surface of the organelle. Here, we show that BH3-only BIK activates this pathway at the ER in intact cells, resulting in mitochondrial fragmentation but little release of cytochrome c to the cytosol. The BIK-induced transformations in mitochondria are dynamic in nature and involve DRP1-dependent remodelling and opening of cristae, where the major stores of cytochrome c reside. This novel function for DRP1 is distinct from its recognized role in regulating mitochondrial fission. Selective permeabilization of the outer membrane with digitonin confirmed that BIK stimulation results in mobilization of intramitochondrial cytochrome c. Of note, BIK can cooperate with a weak BH3-only protein that targets mitochondria, such as NOXA, to activate BAX by a mechanism that is independent of DRP1 enzyme activity. When expressed together, BIK and NOXA cause rapid release of mobilized cytochrome c and activation of caspases.
引用
收藏
页码:1546 / 1556
页数:11
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