AUTHOR=Contino Sabrina , Suelves Nuria , Vrancx Céline , Vadukul Devkee M. , Payen Valery L. , Stanga Serena , Bertrand Luc , Kienlen-Campard Pascal 

TITLE=Presenilin-Deficient Neurons and Astrocytes Display Normal Mitochondrial Phenotypes

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 14 - 2020

YEAR=2021

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2020.586108

DOI=10.3389/fnins.2020.586108

ISSN=1662-453X

ABSTRACT=Presenilins 1 and 2 (PS1 and PS2) are predominantly known as the catalytic subunits of the γ-secretase complex which generates the amyloid-β (Aβ) peptide, the major constituent of the senile plaques found in the brain of Alzheimer's disease (AD) patients. Apart from their role in γ-secretase activity, a growing number of cellular functions have been recently attributed to PSs. Notably, PSs were found to be enriched in mitochondria-associated membranes (MAMs) where mitochondria and endoplasmic reticulum (ER) interact. PS2 was more specifically reported to regulate calcium shuttling between these two organelles by controlling the formation of functional MAMs. We have previously demonstrated in Mouse Embryonic Fibroblasts (MEFs) that an altered mitochondrial morphology along with reduced mitochondrial respiration and increased glycolysis in PS2-dficient cells (PS2KO). This phenotype was restored by the stable re-expression of human PS2. Still, all these results were obtained in immortalized cells, and one bottom-line question is to know whether these observations hold true in Central Nervous System (CNS) cells. To that end, we carried out primary cultures of PS1KO, PS2KO and PS1/PS2KO (PSdKO) neurons and astrocytes. They were obtained from the same litter by crossing PS2 heterozygous (+/-) and PS1 floxed (PS2+/-; PS1flox/flox) animals. Genetic deletion of PS1 was achieved by lentiviral expression of the Cre recombinase in primary cultures. Strikingly, we did not observe any mitochondrial phenotype in PS1KO, PS2KO or PSdKO primary cultures in basal conditions. Mitochondrial respiration and membrane potential were similar in all models, as were the glycolytic flux and NAD+/NADH ratio. We further investigated the differences between results we obtained here in primary nerve cells and those previously reported in MEFs cell lines by analyzing PS2KO primary fibroblasts. We found no mitochondrial dysfunction in this model, in line with observations in PS2KO primary neurons and astrocytes. Together, our results indicate that the mitochondrial phenotype observed in immortalized PS2-deficient cell lines cannot be extrapolated to primary neurons, astrocytes and even to primary fibroblasts. The PS-dependent mitochondrial phenotype reported so far might therefore be the consequence of a cell immortalization process and should be critically reconsidered regarding its relevance to AD.