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

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.