The gain-of-function enhancement of IP3-receptor channel gating by familial Alzheimer's disease-linked presenilin mutants increases the open probability of mitochondrial permeability transition pore

Mutants in presenilins (PS1 or PS2) are the major cause of familial Alzheimer's disease (FAD). They affect intracellular Ca2+ homeostasis by increasing the open probability (P-o) of inositol 1,4,5-trisposphate (IP3) receptor (IP3R) Ca2+ release channel located on the endoplasmic reticulum (ER) leading to exaggerated Ca2+ release into a cytoplasmic microdomain formed by neighboring cluster of a few IP3R channels and mitochondrial Ca2+ uniporter (MCU). Ca2+ concentration in the microdomain ([Ca2+](mic)) depends on the distance between the cluster and MCU (r); the number of IP3R in the cluster releasing Ca2+ to the cytoplasm (n(IP3)R), and P-o of IP3R. Using experimental whole-cell IP3R-mediated cytosolic Ca2+ 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 Ca2+ uptake in cells expressing wild type (PS1-WT) and FAD-causing mutant (PS1-M146L) PS. We find that increased mitochondrial [Ca2+](m) 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 n(IP3)R. Furthermore, we observe diminished inner mitochondrial membrane potential (Delta psi(m)), [NADH], [Ca2+](m), and [ATP] when PTP opens. Additionally, we explore how parameters such as the pH gradient, inorganic phosphate concentration, and the rate of the Na+/Ca2+-exchanger affect the latency of PTP to open in PTPh. (C) 2016 Elsevier Ltd. All rights reserved.