title: Impaired mitochondrial function due to familial Alzheimer's disease-causing presenilins mutants via Ca(2+) disruptions.
abstract: Mutants in presenilins (PS1 or PS2) is the major cause of familial Alzheimer's disease (FAD). FAD causing PS mutants affect intracellular Ca(2+) homeostasis by enhancing the gating of inositol trisphosphate (IP3) receptor (IP3R) Ca(2+) release channel on the endoplasmic reticulum, leading to exaggerated Ca(2+) release into the cytoplasm. Using experimental IP3R-mediated Ca(2+) release data, in conjunction with a computational model of cell bioenergetics, we explore how the differences in mitochondrial Ca(2+) uptake in control cells and cells expressing FAD-causing PS mutants affect key variables such as ATP, reactive oxygen species (ROS), NADH, and mitochondrial Ca(2+). We find that as a result of exaggerated cytosolic Ca(2+) in FAD-causing mutant PS-expressing cells, the rate of oxygen consumption increases dramatically and overcomes the Ca(2+) 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 Ca(2+) signaling disruption, mutant PS leads to mitochondrial dysfunction and potentially to cell death.
authors.affiliation: Department of Physics, University of South Florida, Tampa, FL 33620, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Toglia
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong.
authors.forename: King-Ho
authors.initials: KH
authors.lastname: Cheung
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Don-On Daniel
authors.initials: DO
authors.lastname: Mak
authors.affiliation: Department of Physics, University of South Florida, Tampa, FL 33620, United States. Electronic address: gullah@usf.edu.
authors.forename: Ghanim
authors.initials: G
authors.lastname: Ullah
mesh_terms: D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D015640:Ion Channel Gating / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism*
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D002118:Calcium
keywords: Alzheimer's disease; Ca(2+) signaling; Cell death; IP(3)-receptor; Mitochondria; Presenilins