CaMKII determines mitochondrial stress responses in heart.
CaMKII determines mitochondrial stress responses in heart.
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DOI：
10.1038/nature11444
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发表时间：
2012-11-08
期刊：
影响因子：
64.8
通讯作者：
Anderson, Mark E.
中科院分区：
文献类型：
--
作者：
Joiner, Mei-ling A.;Koval, Olha M.;Li, Jingdong;He, B. Julie;Allamargot, Chantal;Gao, Zhan;Luczak, Elizabeth D.;Hall, Duane D.;Fink, Brian D.;Chen, Biyi;Yang, Jinying;Moore, Steven A.;Scholz, Thomas D.;Strack, Stefan;Mohler, Peter J.;Sivitz, William I.;Song, Long-Sheng;Anderson, Mark E.
心肌细胞死亡是由线粒体内钙过多进入引起的，导致钙超载，线粒体通透性转换孔（mPTP）开放和线粒体内膜电位（Δ Pm）耗散。然而，控制线粒体Ca 2+通过内膜线粒体Ca 2+单向转运体（MCU）进入的信号传导途径尚不清楚。多功能钙离子和钙调素依赖性蛋白激酶II（CaMKII）在缺血再灌注（I/R）、心肌梗死（MI）和神经体液损伤（心肌死亡和心力衰竭的常见原因）中被激活，表明CaMKII可将疾病应激与线粒体损伤偶联。在这里，我们表明，CaMKII通过增加MCU电流（IMCU）促进mPTP开放和心肌死亡。线粒体靶向CaMKII抑制蛋白或环孢菌素A（CsA）是一种在I/R损伤中具有临床疗效的mPTP拮抗剂，可等效地防止mPTP开放、Δ m恶化，并减少线粒体破坏和响应I/R损伤的程序性细胞死亡。具有心肌和脑靶向CaMK II抑制的小鼠对I/R损伤、MI和神经体液损伤具有抗性，表明CaMK II的病理作用实质上是通过增加IMCU介导的。我们的研究结果确定CaMKII活性是线粒体Ca 2+进入的核心机制，并表明线粒体靶向CaMKII抑制可以预防或减少心肌死亡和心力衰竭功能障碍，以应对常见实验形式的病理生理应激。
Myocardial cell death is initiated by excessive mitochondrial Ca2+ entry, causing Ca2+ overload, mitochondrial permeability transition pore (mPTP) opening and dissipation of the mitochondrial inner membrane potential (ΔΨm). However, the signaling pathways that control mitochondrial Ca2+ entry through the inner membrane mitochondrial Ca2+ uniporter (MCU) are not known. The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is activated in ischemia reperfusion (I/R), myocardial infarction (MI) and neurohumoral injury, common causes of myocardial death and heart failure, suggesting CaMKII could couple disease stress to mitochondrial injury. Here we show that CaMKII promotes mPTP opening and myocardial death by increasing MCU current (IMCU). Mitochondrial-targeted CaMKII inhibitory protein or cyclosporin A (CsA), an mPTP antagonist with clinical efficacy in I/R injury, equivalently prevent mPTP opening, ΔΨm deterioration and diminish mitochondrial disruption and programmed cell death in response to I/R injury. Mice with myocardial and mitochondrial-targeted CaMKII inhibition are resistant to I/R injury, MI and neurohumoral injury, suggesting pathological actions of CaMKII are substantially mediated by increasing IMCU. Our findings identify CaMKII activity as a central mechanism for mitochondrial Ca2+ entry and suggest mitochondrial-targeted CaMKII inhibition could prevent or reduce myocardial death and heart failure dysfunction in response to common experimental forms of pathophysiological stress.
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影响因子：
15.9
作者：
Timmins, Jenelle M.;Ozcan, Lale;Tabas, Ira
通讯作者：
Tabas, Ira
影响因子：
4.8
作者：
Olichon, A;Baricault, L;Lenaers, G
通讯作者：
Lenaers, G
影响因子：
15.9
作者：
Singh, Madhu V.;Kapoun, Ann;Anderson, Mark E.
通讯作者：
Anderson, Mark E.
影响因子：
4.3
作者：
Sharma, Vijay;Abraham, Thomas;McNeill, John H.
通讯作者：
McNeill, John H.
DOI：
10.1073/pnas.051449198
发表时间：
2001-02-27
影响因子：
11.1
作者：
Wu, YJ;Colbran, RJ;Anderson, ME
通讯作者：
Anderson, ME