Impaired Mitochondrial Function due to Familial Alzheimers Disease-Causing Presenilins Mutants via Calcium Disruptions

Authors

Patrick T. Toglia, University of South Florida
King-Ho Cheung, University of Hong Kong
Don-On Daniel Mak, University of Hong Kong
Ghamim Ullah, University of South FloridaFollow

Document Type

Article

Publication Date

2-16-2016

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.bpj.2015.11.1670

Abstract

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 (PTP_h) 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 PTP_h 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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Yes

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.
https://digitalcommons.usf.edu/phy_facpub/25