Endoplasmic reticulum-mitochondria crosstalk in NIX-mediated murine cell death
Endoplasmic reticulum-mitochondria crosstalk in NIX-mediated murine cell death
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DOI：
10.1172/jci36445
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发表时间：
2009-01-01
影响因子：
15.9
通讯作者：
Dorn, Gerald W., II
中科院分区：
文献类型：
--
作者：
Diwan, Abhinav;Matkovich, Scot J.;Dorn, Gerald W., II
促凋亡BCL 2家族蛋白NIX的转录上调限制了红细胞形成，并可通过诱导细胞死亡引起心力衰竭，但所需的分子事件定义不清。在这里，我们展示了NIX介导的细胞死亡的互补机制，包括直接和ER/肌浆网介导的（ER/SR介导的）线粒体破坏。内源性心脏NIX和重组NIX定位于线粒体和ER/SR。在遗传小鼠模型中，心肌细胞ER/SR钙储存与表达NIX的水平成比例。尽管Nix消融在凋亡性心肌病小鼠模型中具有保护作用，但对Nix缺失小鼠SR钙含量降低的遗传校正恢复了对细胞死亡的敏感性并重建了心肌病。特异于ER/SR或线粒体的Nix突变体激活半胱天冬酶，并且同样致命，但只有ER/SR-Nix引起线粒体膜电位的损失。这些结果建立了一个新的功能，NIX作为一个整合器的转录和钙介导的信号程序性细胞死亡。
Transcriptional upregulation of the proapoptotic BCL2 family protein NIX limits red blood cell formation and can cause heart failure by inducing cell death, but the requisite molecular events are poorly defined. Here, we show complementary mechanisms for NIX-mediated cell death involving direct and ER/sarcoplasmic reticulum-mediated (ER/SR-mediated) mitochondria disruption. Endogenous cardiac NIX and recombinant NIX localize both to the mitochondria and to the ER/SR. In genetic mouse models, cardiomyocyte ER/SR calcium stores are proportional to the level of expressed NIX. Whereas Nix ablation was protective in a mouse model of apoptotic cardiomyopathy, genetic correction of the decreased SR calcium content of Nix-null mice restored sensitivity to cell death and reestablished cardiomyopathy. Nix mutants specific to ER/SR or mitochondria activated caspases and were equally lethal, but only ER/SR-Nix caused loss of the mitochondrial membrane potential. These results establish a new function for NIX as an integrator of transcriptional and calcium-mediated signals for programmed cell death.