Qi Hong, Li Linxi, Shuai Jianwei
Department of Physics, Xiamen University, Xiamen 361005, China.
1] Department of Physics, Xiamen University, Xiamen 361005, China [2] State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, Xiamen University, Xiamen 361005, China [3] Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, Xiamen University, Xiamen 361005, China.
Sci Rep. 2015 Jan 23;5:7984. doi: 10.1038/srep07984.
A Ca(2+) signaling model is proposed to consider the crosstalk of Ca(2+) ions between endoplasmic reticulum (ER) and mitochondria within microdomains around inositol 1, 4, 5-trisphosphate receptors (IP3R) and the mitochondrial Ca(2+) uniporter (MCU). Our model predicts that there is a critical IP3R-MCU distance at which 50% of the ER-released Ca(2+) is taken up by mitochondria and that mitochondria modulate Ca(2+) signals differently when outside of this critical distance. This study highlights the importance of the IP3R-MCU distance on Ca(2+) signaling dynamics. The model predicts that when MCU are too closely associated with IP3Rs, the enhanced mitochondrial Ca(2+) uptake will produce an increase of cytosolic Ca(2+) spike amplitude. Notably, the model demonstrates the existence of an optimal IP3R-MCU distance (30-85 nm) for effective Ca(2+) transfer and the successful generation of Ca(2+) signals in healthy cells. We suggest that the space between the inner and outer mitochondria membranes provides a defense mechanism against occurrences of high [Ca(2+)]Cyt. Our results also hint at a possible pathological mechanism in which abnormally high [Ca(2+)]Cyt arises when the IP3R-MCU distance is in excess of the optimal range.
我们提出了一种钙离子信号模型，以考虑内质网（ER）和线粒体之间钙离子在肌醇1,4,5-三磷酸受体（IP3R）和线粒体钙离子单向转运体（MCU）周围微区中的相互作用。我们的模型预测，存在一个关键的IP3R-MCU距离，在此距离下，内质网释放的50%的钙离子会被线粒体摄取，并且当超出此关键距离时，线粒体对钙离子信号的调节方式会有所不同。这项研究突出了IP3R-MCU距离对钙离子信号动态变化的重要性。该模型预测，当MCU与IP3R联系过于紧密时，线粒体钙离子摄取的增强会导致胞质钙离子尖峰幅度增加。值得注意的是，该模型证明了存在一个最佳的IP3R-MCU距离（30 - 85纳米），以实现有效的钙离子转移并在健康细胞中成功产生钙离子信号。我们认为线粒体内外膜之间的空间提供了一种抵御高胞质钙离子浓度出现的防御机制。我们的结果还暗示了一种可能的病理机制，即当IP3R-MCU距离超过最佳范围时，会出现异常高的胞质钙离子浓度。
