Model of mitochondrial function

多个细胞器紧密协调细胞内Ca2+动态，以调节细胞活动和维持体内平衡。内质网（ER）是细胞内Ca2+的主要储存库，而线粒体是三磷酸腺苷（ATP）的重要来源，它们之间的相互作用一直是许多研究的主题。有趣的是，在整个细胞质结构域中，这两个细胞器共享称为线粒体相关ER膜（MAMs）的共同微结构域，它们的膜紧密相连。MAMs的作用对细胞内Ca2+动力学至关重要，因为它们为细胞器之间的直接Ca2+交换提供了必要的枢纽。最近的一项实验研究报道，肥胖小鼠的肝细胞具有与健康动物不同的细胞特性，特别是MAM的形成程度，ER膜上Ca2+释放通道和线粒体膜上Ca2+隔离通道的表达水平，并观察到它们表现出不同的Ca2+动力学。我们建立了一个数学模型来研究MAM Ca2+动态对全局Ca2+活性的影响。通过一系列模型模拟，我们研究了肥胖细胞中Ca2+动力学改变的细胞机制。我们发现MAMs的形成与细胞质Ca2+活性的振幅呈负相关，但与线粒体Ca2+动力学和Ca2+振荡的总体频率呈正相关。ER Ca2+释放通道的过表达增加了两种细胞器的Ca2+振幅，以及振荡频率。最后，上调线粒体Ca2+通道增加了线粒体Ca2+活动的幅度，同时降低了细胞质Ca2+活动的幅度。有趣的是，振荡频率降低了。总之，我们模拟了肥胖、MAMs和肝脏Ca2+动态之间的联系。该模型反映了对照组小鼠和遗传性肥胖小鼠肝细胞之间的细胞差异，并成功地复制了实验追踪的肝脏Ca2+活性。我们的模型模拟预测，肥胖小鼠的肝细胞产生Ca2+振荡，与对照小鼠相比，在较高浓度的刺激下，这种振荡不太可能持续。

Multiple cellular organelles tightly orchestrate intracellular Ca2+ dynamics to regulate cellular activities and maintain homeostasis. The interplay between the endoplasmic reticulum (ER), a major store of intracellular Ca2+, and mitochondria, an important source of adenosine triphos- phate (ATP), has been the subject of much research. Interestingly, throughout the cells cytosolic domain, these two organelles share common microdomains called mitochondria-associated ER mem- branes (MAMs), where their membranes are in close apposition. The role of MAMs is critical for intracellular Ca2+ dynamics as they provide essential hubs for direct Ca2+ exchange between the organelles. A recent experimental study reported that liver cells from obese mice have different cellular properties from those of healthy animals, in particular, the degree of MAM formation, the expression levels of Ca2+ releasing channels on the ER membrane and that of Ca2+ sequestering channels on mitochondrial membrane, and observed that they exhibit different Ca2+ dynamics. We constructed a mathematical model to study the effects of MAM Ca2+ dynamics on global Ca2+ activities. Through a series of model simulations, we investigated cellular mechanisms underlying the altered Ca2+ dynamics in the cells under obesity. We found that the formation of MAMs is negatively correlated with the amplitude of cytosolic Ca2+ activities, but positively correlated with that of mitochondrial Ca2+ dynamics and the overall frequency of Ca2+ oscillations. The over-expression of ER Ca2+ releasing channels increased Ca2+ amplitudes in both organelles, as well as the oscillation frequency. Lastly, up-regulating mitochondrial Ca2+ channels increased the magnitude of mitochondrial Ca2+ activities, while decreasing that of cytosolic Ca2+ activities. Interestingly, the oscillation frequency was decreased. In conclusion, we modeled the link between obesity, MAMs, and hepatic Ca2+ dynamics. The model reflected the cellular differences between hepatocytes from control mice and those from genetically obese mice, and successfully reproduced experimentally traced hepatic Ca2+ activities. Our model simulation predicts that hepatocytes from obese mice generate Ca2+ oscillations that are less likely to be sustained under higher concentrations of stimulus, compared to those from control mice.