Impaired mitochondrial function due to familial Alzheimer's disease-causing presenilins mutants via Ca2+ disruptions

Patrick Toglia, King Ho Cheung, Don On Daniel Mak, Ghanim Ullah*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

29 Citations (Scopus)

Abstract

Mutants in presenilins (PS1 or PS2) is the major cause of familial Alzheimer's disease (FAD). FAD causing PS mutants affect intracellular Ca2+ homeostasis by enhancing the gating of inositol trisphosphate (IP3) receptor (IP3R) Ca2+ release channel on the endoplasmic reticulum, leading to exaggerated Ca2+ release into the cytoplasm. Using experimental IP3R-mediated Ca2+ release data, in conjunction with a computational model of cell bioenergetics, we explore how the differences in mitochondrial Ca2+ uptake in control cells and cells expressing FAD-causing PS mutants affect key variables such as ATP, reactive oxygen species (ROS), NADH, and mitochondrial Ca2+. We find that as a result of exaggerated cytosolic Ca2+ in FAD-causing mutant PS-expressing cells, the rate of oxygen consumption increases dramatically and overcomes the Ca2+ dependent enzymes that stimulate NADH production. This leads to decreased rates in proton pumping due to diminished membrane potential along with less ATP and enhanced ROS production. These results show that through Ca2+ signaling disruption, mutant PS leads to mitochondrial dysfunction and potentially to cell death.

Original languageEnglish
Pages (from-to)240-250
Number of pages11
JournalCell Calcium
Volume59
Issue number5
DOIs
Publication statusPublished - May 2016
Externally publishedYes

User-Defined Keywords

  • Mitochondria
  • Ca2+ signaling
  • Presenilins
  • Cell death
  • Alzheimer's disease
  • IP3-receptor

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