Endoplasmic reticulum-mitochondria crosstalk in NIX-mediated murine cell death

被引：136

作者：

Diwan, Abhinav ^{[1
]}

Matkovich, Scot J. ^{[1
]}

Yuan, Qunying ^{[2
]}

Zhao, Wen ^{[2
]}

Yatani, Atsuko ^{[3
]}

Brown, Joan Heller ^{[4
]}

Molkentin, Jeffery D. ^{[5
]}

Kranias, Evangelia G. ^{[2
]}

Dorn, Gerald W., II ^{[1
,2
]}

机构：

[1] Washington Univ, Ctr Pharmacogen, St Louis, MO 63110 USA

[2] Univ Cincinnati, Dept Pharmacol & Cell Biophys, Cincinnati, OH 45267 USA

[3] Univ Med & Dent New Jersey, Dept Surg, Newark, NJ 07103 USA

[4] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA

[5] Cincinnati Childrens Hosp, Dept Pediat, Cincinnati, OH USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2009年 / 119卷 / 01期

关键词：

BCL-2; FAMILY-MEMBERS; SARCOPLASMIC-RETICULUM; CARDIAC-HYPERTROPHY; BH3-ONLY PROTEINS; INOSITOL 1,4,5-TRISPHOSPHATE; PERMEABILITY TRANSITION; VENTRICULAR MYOCYTES; CA2+ CONCENTRATION; DISTINCT PATHWAYS; PROAPOPTOTIC BAX;

D O I：

10.1172/JCI36445

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：203 / 212

页数：10

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