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. Issue 1 (July 2016)

• Record Type: Journal Article
• Authors: Toglia, Patrick; Ullah, Ghanim
• Is Part Of: Cell calcium. Volume 60:Issue 1(2016)
• Page Start: 13
• Page End: 24
• Publication Date: 2016-07
• Subjects: Presenilins -- Alzheimer's disease -- Mitochondria -- Permeability transition pore -- Cell death -- Apoptosis; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2016.05.002
• Languages: English
• ISSNs: 0143-4160

Abstract

Abstract : Graphical abstract: Abstract : Highlights: Higher ΔpH increases the latency of PTP openings. Pi sensitizes PTP. Na + /Ca 2+ exchanger rate influences PTP opening latency. Abstract: 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 ( P o ) of inositol 1, 4, 5-trisposphate (IP3 ) receptor (IP3 R) 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 IP3 R channels and mitochondrial Ca 2+ uniporter (MCU). Ca 2+ concentration in the microdomain ( [ Ca 2 + ] mic ) depends on the distance between the cluster and MCU ( r ); the number of IP3 R in the cluster releasing Ca 2+ to the cytoplasm ( n IP 3 R ), and P o of IP3 R. Using experimental whole-cell IP3 R-mediated cytosolic Ca 2+ data, in conjunction with a computational model of cell bioenergetics, a data-driven Markov chain model for IP3 R 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 [ Ca 2 + ] m due to the gain-of-function enhancement of IP3 R channels in the cells expressing PS1-M146L leads to the opening of PTP in high conductance state (PTP h ), where the latency of opening is inversely correlated with r and proportional to n IP 3 R . Furthermore, we observe diminished inner mitochondrial membrane potential (Δ Ψ m ), [NADH], [ Ca 2 + ] 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 + /Ca 2+ -exchanger affect the latency of PTP to open in PTP h .