Institute of Neuroscience, Italian National Research Council (CNR), Viale G. Colombo 3, 35121 Padova, Italy; Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy.
Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy.
Cell Metab. 2013 Jun 4;17(6):965-975. doi: 10.1016/j.cmet.2013.05.003.
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.
虽然线粒体钙离子稳态在细胞病理生理学中的作用已被广泛接受，但 cAMP 调节线粒体功能的可能性最近才得到实验支持。cAMP 产生的部位、其靶标以及其在细胞器中的功能仍不确定。在这里，我们使用多种遗传/药理学工具证明，细胞质中的 cAMP 无法穿过线粒体的内膜，而自主的 cAMP 信号工具包则在基质中表达。我们证明，基质中的 Ca²⁺ 升高会强烈刺激线粒体中 cAMP 的增加，并且基质中的 cAMP 水平调节它们的 ATP 合成效率。在心肌细胞培养物中，通过增加细胞质和细胞器中 Ca²⁺ 震荡的频率和幅度的处理，可以增加线粒体中的 cAMP，这表明线粒体可以整合一个震荡的 Ca²⁺ 信号来增加其基质中的 cAMP。目前的数据揭示了在先前未知的线粒体中存在 Ca²⁺ 和 cAMP 之间的串扰。
