title: 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.
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 (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.
authors.affiliation: Department of Physics, University of South Florida, Tampa, FL 33620, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Toglia
authors.affiliation: Department of Physics, University of South Florida, Tampa, FL 33620, USA. Electronic address: gullah@usf.edu.
authors.forename: Ghanim
authors.initials: G
authors.lastname: Ullah
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D002118:Calcium / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D015640:Ion Channel Gating; D008928:Mitochondria; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009154:Mutation / Q000235:genetics*; D053763:Presenilins / Q000235:genetics*; D011336:Probability; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013997:Time Factors
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D053763:Presenilins; D019831:Sodium-Calcium Exchanger; D002118:Calcium
keywords: Alzheimer's disease; Apoptosis; Cell death; Mitochondria; Permeability transition pore; Presenilins