Digital Object Identifier (DOI)
Muatans in presenilins (PS1 or PS2) is the major cause of Familial Alzheimer's disease (FAD). FAD causing PS mutants affect intracellular Ca2+ ([Ca2+]i) homeostasis by enhancing the gating of inositol trisphosphate (IP3) receptor (IP3R) Ca2+ release channels on the endoplasmic reticulum (ER), leading to exaggerated Ca2+ release into the cytoplasm (Cheung et al., Neuron 2008:871, Sci. Signal 2010:ra22). Using experimental IP3R-mediated Ca2+ release data, in conjunction with a computational model of cell bioenergetics (Cortassa et al., Biophys. J. 2003:2734, 2004:2067), we explore how the differences in mitochondrial Ca2+ uptake in control PS1-WT and cells expressing FAD causing PS1-M146L mutant affect key variables such as ATP, reactive oxygen species (ROS), NADH, and mitochondrial calcium ([Ca2+]m). Furthermore, we extend the model to include a high-conductance permeability transition pore (PTPh) that depends on the Ca2+ in the microdomain ([Ca]2+mic) specified by the distance between ER and mitochondrial uniporter together with a data-driven single IP3R model (Mak et al., PLoS Comp. 2015:in press) to show that the exaggerated [Ca2+]i in cells expressing PS1-M146L, significantly diminished NADH production because of increased oxygen consumption. This leads to a decrease in the rates in proton pumping due to diminished membrane potential, along with less ATP and enhanced ROS production. Once a critical level of [Ca2+]m is reached, we observe PTPh openings that further lead to mitochondrial dysfunction. These results show that through Ca2+ signaling disruption, mutant PS leads to mitochondrial dysfunction and cell death.
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Citation / Publisher Attribution
Biophysical Journal, v. 110, issue 3, supplement 1, p. 311a
This article is the post-print author version.
Scholar Commons Citation
Toglia, Patrick T.; Cheung, King-Ho; Mak, Don-On Daniel; and Ullah, Ghamim, "Impaired Mitochondrial Function due to Familial Alzheimers Disease-Causing Presenilins Mutants via Calcium Disruptions" (2016). Physics Faculty Publications. 25.