Differential Role of Presenilin-1 and -2 on Mitochondrial Membrane Potential and Oxygen Consumption in Mouse Embryonic Fibroblasts.
From: Department of Neurobiology, Karolinska Institutet Dainippon Sumitomo Pharmaceuticals Alzheimer Center, Caring Sciences and Society, Novum, Huddinge, Sweden. homira.behbahani@ki.se
Journal of neuroscience research
- Publish Date: Sep 2006
- ISSN: 0360-4012
- Volume: 84
- Issue: 4
- Pages: 891-902
- Medium: Print
- Language: English
- Citation (JAMA): Behbahani Homira, Shabalina Irina G, Wiehager Birgitta, et al. Differential Role of Presenilin-1 and -2 on Mitochondrial Membrane Potential and Oxygen Consumption in Mouse Embryonic Fibroblasts.. J. Neurosci. Res. Sep 2006;84:891-902
Abstract
Increasing evidence indicates that mitochondrial alterations contribute to the neuronal death in Alzheimer’s disease (AD). Presenilin 1 (PS1) and Presenilin 2 (PS2) mutations have been shown to sensitize cells to apoptosis by mechanisms suggested to involve impaired mitochondrial function. We have previously detected active gamma-secretase complexes in mitochondria. We investigated the impact of PS/gamma-secretase on mitochondrial function using mouse embryonal fibroblasts derived from wild-type, PS1-/-, PS2-/- and PS double knock-out (PSKO) embryos. Measurements of mitochondrial membrane potential (DeltaPsim) showed a higher percentage of fully functional mitochondria in PS1-/- and PSwt as compared to PS2-/- and PSKO cells. This result was evident both in whole cell preparations and in isolated mitochondria. Interestingly, pre-treatment of isolated mitochondria with the gamma-secretase inhibitor L-685,458 resulted in a decreased population of mitochondria with high DeltaPsim in PSwt and PS1-/- cells, indicating that PS2/gamma-secretase activity can modify DeltaPsim. PS2-/- cells showed a significantly lower basal respiratory rate as compared to other cell lines. However, all cell lines demonstrated competent bioenergetic function. These data point toward a specific role of PS2/gamma-secretase activity for proper mitochondrial function and indicate interplay between PS1 and PS2 in mitochondrial functionality.
Mesh Headings (Keywords): Adenosine Triphosphate, Analysis of Variance, Animals, Benzimidazoles, Carbocyanines, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone, Cells, Cultured, Dose-Response Relationship, Drug, Drug Interactions, Embryo, Mammalian, Enzyme Inhibitors, Fibroblasts, Flow Cytometry, Ionophores, Membrane Potentials, Membrane Proteins, Mice, Mice, Knockout, Mitochondrial Membranes, Oligomycins, Oxygen Consumption, Presenilin-1, Presenilin-2
Check for Full Text / PubMed Unique Identifier (PMID): 16883555
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