Toglia Patrick, Ullah Ghanim
Department of Physics, University of South Florida, Tampa, FL 33620, USA.
Department of Physics, University of South Florida, Tampa, FL 33620, USA.
Cell Calcium. 2016 Jul;60(1):13-24. doi: 10.1016/j.ceca.2016.05.002. Epub 2016 May 7.
Mutants in presenilins (PS1 or PS2) are the major cause of familial Alzheimer's disease (FAD). They affect intracellular Ca(2+) homeostasis by increasing the open probability (Po) of inositol 1,4,5-trisposphate (IP3) receptor (IP3R) Ca(2+) release channel located on the endoplasmic reticulum (ER) leading to exaggerated Ca(2+) release into a cytoplasmic microdomain formed by neighboring cluster of a few IP3R channels and mitochondrial Ca(2+) uniporter (MCU). Ca(2+) concentration in the microdomain ( [Formula: see text] ) depends on the distance between the cluster and MCU (r); the number of IP3R in the cluster releasing Ca(2+) to the cytoplasm ( [Formula: see text] ), and Po of IP3R. Using experimental whole-cell IP3R-mediated cytosolic Ca(2+) data, in conjunction with a computational model of cell bioenergetics, a data-driven Markov chain model for IP3R gating, and a model for the dynamics of the mitochondrial permeability transition pore (PTP), we explore differences in mitochondrial Ca(2+) uptake in cells expressing wild type (PS1-WT) and FAD-causing mutant (PS1-M146L) PS. We find that increased mitochondrial [Formula: see text] due to the gain-of-function enhancement of IP3R channels in the cells expressing PS1-M146L leads to the opening of PTP in high conductance state (PTPh), where the latency of opening is inversely correlated with r and proportional to [Formula: see text] . Furthermore, we observe diminished inner mitochondrial membrane potential (ΔΨm), [NADH], [Formula: see text] , and [ATP] when PTP opens. Additionally, we explore how parameters such as the pH gradient, inorganic phosphate concentration, and the rate of the Na(+)/Ca(2+)-exchanger affect the latency of PTP to open in PTPh.
早老素（PS1或PS2）突变体是家族性阿尔茨海默病（FAD）的主要病因。它们通过增加位于内质网（ER）上的肌醇1,4,5-三磷酸（IP3）受体（IP3R）Ca(2+)释放通道的开放概率（Po）来影响细胞内Ca(2+)稳态，导致Ca(2+)过度释放到由相邻几个IP3R通道簇和线粒体Ca(2+)单向转运体（MCU）形成的细胞质微区。微区内的Ca(2+)浓度（[公式：见正文]）取决于簇与MCU之间的距离（r）；簇中向细胞质释放Ca(2+)的IP3R数量（[公式：见正文]）以及IP3R的Po。利用实验性全细胞IP3R介导的胞质Ca(2+)数据，结合细胞生物能学计算模型、IP3R门控的数据驱动马尔可夫链模型以及线粒体通透性转换孔（PTP）动力学模型，我们探究了表达野生型（PS1-WT）和导致FAD的突变型（PS1-M146L）PS的细胞中线粒体Ca(2+)摄取的差异。我们发现，由于表达PS1-M146L的细胞中IP3R通道功能增强导致线粒体[公式：见正文]增加，从而导致PTP在高电导状态（PTPh）下开放，其中开放潜伏期与r成反比且与[公式：见正文]成正比。此外，我们观察到PTP开放时线粒体内膜电位（ΔΨm）、[NADH]、[公式：见正文]和[ATP]降低。此外，我们还探究了诸如pH梯度、无机磷酸盐浓度以及Na(+)/Ca(2+)交换器速率等参数如何影响PTP在PTPh中开放的潜伏期。
