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Differential role of presenilin‐1 and ‐2 on mitochondrial membrane potential and oxygen consumption in mouse embryonic fibroblasts
Author(s) -
Behbahani Homira,
Shabalina Irina G.,
Wiehager Birgitta,
Concha Hérnan,
Hultenby Kjell,
Petrovic Natasa,
Nedergaard Jan,
Winblad Bengt,
Cowburn Richard F.,
Ankarcrona Maria
Publication year - 2006
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20990
Subject(s) - presenilin , mitochondrion , microbiology and biotechnology , biology , bioenergetics , membrane potential , programmed cell death , mitochondrial apoptosis induced channel , cell , apoptosis , embryonic stem cell , inner mitochondrial membrane , biochemistry , alzheimer's disease , medicine , disease , gene
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 γ‐secretase complexes in mitochondria. We investigated the impact of PS/γ‐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 (ΔΨm) 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 γ‐secretase inhibitor L‐685,458 resulted in a decreased population of mitochondria with high ΔΨm in PSwt and PS1−/− cells, indicating that PS2/γ‐secretase activity can modify ΔΨm. 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/γ‐secretase activity for proper mitochondrial function and indicate interplay between PS1 and PS2 in mitochondrial functionality. © 2006 Wiley‐Liss, Inc.