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

• FAD causing PS mutants cause enhanced Ca2+ release resulting in impaired mitochondrial function.
• Exaggerated Ca2+ absorption depolarizes mitochondrial membrane potential, reducing proton pumping.
• ATP production decreases in cells expressing FAD causing PS-mutants.
• ROS production increases in FAD causing PS-mutant cells due to enhanced oxygen consumption.

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.

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