Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways

被引:393
作者
Timmins, Jenelle M. [1 ]
Ozcan, Lale [1 ]
Seimon, Tracie A. [1 ]
Li, Gang [1 ]
Malagelada, Cristina [2 ,3 ,4 ]
Backs, Johannes [5 ]
Backs, Thea [6 ]
Bassel-Duby, Rhonda [6 ]
Olson, Eric N. [6 ]
Anderson, Mark E. [7 ,8 ]
Tabas, Ira [1 ,2 ,9 ]
机构
[1] Columbia Univ, Dept Med, New York, NY 10032 USA
[2] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA
[3] Columbia Univ, Ctr Neurobiol & Behav, New York, NY 10032 USA
[4] Columbia Univ, Taub Ctr Alzheimers Dis Res, New York, NY 10032 USA
[5] Heidelberg Univ, Dept Internal Med 3, Heidelberg, Germany
[6] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA
[7] Univ Iowa, Carver Coll Med, Dept Physiol & Mol Biophys, Iowa City, IA USA
[8] Univ Iowa, Dept Internal Med, Div Cardiovasc Med, Iowa City, IA 52242 USA
[9] Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY USA
关键词
ENDOPLASMIC-RETICULUM STRESS; ADVANCED ATHEROSCLEROTIC LESIONS; CHOLESTEROL-LOADED MACROPHAGES; CARDIAC RYANODINE RECEPTOR; CELL-DEATH; MEMBRANE PERMEABILIZATION; TARGETED DISRUPTION; INHIBITION PROTECTS; PARKINSONS-DISEASE; C-JUN;
D O I
10.1172/JCI38857
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
ER stress-induced apoptosis is implicated in various pathological conditions, but the mechanisms linking ER stress-mediated signaling to downstream apoptotic pathways remain unclear. Using human and mouse cell culture and in vivo mouse models of ER stress-induced apoptosis, we have shown that cytosolic calcium resulting from ER stress induces expression of the Fas death receptor through a pathway involving calcium/calmodulin-dependent protein kinase II gamma (CaMKII gamma) and JNK. Remarkably, CaMKII gamma was also responsible for processes involved in mitochondrial-dependent apoptosis, including release of mitochondrial cytochrome c and loss of mitochondrial membrane potential. CaMKII-dependent apoptosis was also observed in a number of cultured human and mouse cells relevant to ER stress-induced pathology, including cultured macrophages, endothelial cells, and neuronal cells subjected to proapoptotic ER stress. Moreover, WT mice subjected to systemic ER stress showed evidence of macrophage mitochondrial dysfunction and apoptosis, renal epithelial cell apoptosis, and renal dysfunction, and these effects were markedly reduced in CaMKII gamma-deficient mice. These data support an integrated model in which CaMKII serves as a unifying link between ER stress and the Fas and mitochondrial apoptotic pathways. Our study also revealed what we believe to be a novel proapoptotic function for CaMKII, namely, promotion of mitochondrial calcium uptake. These findings raise the possibility that CaMKII inhibitors could be useful in preventing apoptosis in pathological settings involving ER stress-induced apoptosis.
引用
收藏
页码:2925 / 2941
页数:17
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