Department of Biomedical Engineering, Florida International University, Miami, FL, USA.
School of Chemical Engineering, National Technical University of Athens, Athens, Greece.
Sci Rep. 2019 Nov 19;9(1):17072. doi: 10.1038/s41598-019-53440-7.
Upon inositol trisphosphate (IP) stimulation of non-excitable cells, including vascular endothelial cells, calcium (Ca) shuttling between the endoplasmic reticulum (ER) and mitochondria, facilitated by complexes called Mitochondria-Associated ER Membranes (MAMs), is known to play an important role in the occurrence of cytosolic Ca concentration ([Ca]) oscillations. A mathematical compartmental closed-cell model of Ca dynamics was developed that accounts for ER-mitochondria Ca microdomains as the µd compartment (besides the cytosol, ER and mitochondria), Ca influx to/efflux from each compartment and Ca buffering. Varying the distribution of functional receptors in MAMs vs. the rest of ER/mitochondrial membranes, a parameter called the channel connectivity coefficient (to the µd), allowed for generation of [Ca]oscillations driven by distinct mechanisms at various levels of IP stimulation. Oscillations could be initiated by the transient opening of IP receptors facing either the cytosol or the µd, and subsequent refilling of the respective compartment by Ca efflux from the ER and/or the mitochondria. Only under conditions where the µd became the oscillation-driving compartment, silencing the Mitochondrial Ca Uniporter led to oscillation inhibition. Thus, the model predicts that alternative mechanisms can yield [Ca] oscillations in non-excitable cells, and, under certain conditions, the ER-mitochondria µd can play a regulatory role.
在非兴奋细胞（包括血管内皮细胞）中，三磷酸肌醇（IP）刺激时，钙（Ca）通过称为线粒体相关内质网膜（MAMs）的复合物在内质网（ER）和线粒体之间穿梭，这在细胞质 Ca 浓度 ([Ca]) 振荡的发生中起着重要作用。开发了一个 Ca 动力学的数学隔室封闭细胞模型，该模型将 ER-线粒体 Ca 微区室（除了细胞质、ER 和线粒体之外）作为 µd 隔室考虑在内，以及 Ca 从每个隔室的流入/流出和 Ca 缓冲作用。通过改变 MAMs 中功能性受体的分布与 ER/线粒体膜的其余部分相比，一个称为通道连通系数（µd）的参数允许在不同的 IP 刺激水平下通过不同的机制产生 [Ca] 振荡。振荡可以通过面对细胞质或 µd 的 IP 受体的短暂开放来引发，随后通过 ER 和/或线粒体的 Ca 流出来填充相应的隔室。只有在 µd 成为振荡驱动隔室的情况下，沉默线粒体 Ca 单向转运蛋白才会导致振荡抑制。因此，该模型预测，替代机制可以在非兴奋细胞中产生 [Ca] 振荡，并且在某些条件下，ER-线粒体 µd 可以发挥调节作用。
