Mitochondrial Ca2+ Uptake Induces Cyclic AMP Generation in the Matrix and Modulates Organelle ATP Levels
Mitochondrial Ca2+ Uptake Induces Cyclic AMP Generation in the Matrix and Modulates Organelle ATP Levels
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DOI：
10.1016/j.cmet.2013.05.003
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发表时间：
2013-06-04
期刊：
影响因子：
29
通讯作者：
Pozzan, Tullio
中科院分区：
文献类型：
--
作者：
Di Benedetto, Giulietta;Scalzotto, Elisa;Pozzan, Tullio
虽然线粒体钙稳态在细胞病理生理学中的作用被广泛接受，但cAMP调节线粒体功能的可能性直到最近才得到实验支持。CAMP的产生地点、目标及其在细胞器中的功能仍不确定。在这里，我们使用各种遗传/药理学工具，证明线粒体内膜对胞质cAMP是不通透的，而一个自主的cAMP信号工具包在基质中表达。我们证明，基质钙离子的升高强烈地刺激线粒体内cAMP的增加，并且基质cAMP水平调节其ATP合成效率。在心肌细胞培养中，通过增加胞浆和细胞器内钙振荡的频率和幅度可以增加线粒体cAMP，这表明线粒体可以整合振荡的钙信号来增加其基质中的cAMP。目前的数据显示，在线粒体内，钙离子和cAMP之间存在着一种迄今未知的串扰。
While the role of mitochondrial Ca2+ homeostasis in cell pathophysiology is widely accepted, the possibility that cAMP regulates mitochondrial functions has only recently received experimental support. The site of cAMP production, its targets, and its functions in the organelles remain uncertain. Using a variety of genetic/pharmacological tools, we here demonstrate that the mitochondrial inner membrane is impermeable to cytosolic cAMP, while an autonomous cAMP signaling toolkit is expressed in the matrix. We demonstrate that rises in matrix Ca2+ powerfully stimulate cAMP increases within mitochondria and that matrix cAMP levels regulate their ATP synthesizing efficiency. In cardiomyocyte cultures, mitochondrial cAMP can be increased by treatments that augment the frequency and amplitude of Ca2+ oscillations within the cytosol and organelles, revealing that mitochondria can integrate an oscillatory Ca2+ signal to increase cAMP in their matrix. The present data reveal the existence, within mitochondria, of a hitherto unknown crosstalk between Ca2+ and cAMP.