Investigating the role of presenilins in mitochondrial activity and metabolism

Abstract

Presenilines (PS1 & PS2) are known for their involvement in the production of the amyloid β peptide (Aβ) which accumulates and forms the characteristic senile plaques of Alzheimer's disease (AD). In addition to this role, the PSs have been assigned numerous physiological functions. They are enriched in the lipid rafts present at the plasma membrane but also in the sub-compartments called mitochondrial-associated membrane (MAM) where the reticulum and the mitochondria interact to regulate various processes. In this work, we have studied the role of PSs in cell metabolism with a particular interest in mitochondria and lipid metabolism. Preliminary data obtained from fibroblastic lines deficient in PSs show that PSs could be involved in endocytosis and extracellular vesicles formation. These processes are currently widely studied for their potential role in the spread of Aβ. We also observed a PS2-dependent phenotype only in these cell lines. Indeed, the activity and expression of the electron transport chain was deficient, as was the NAD+/NADH ratio. Anaerobic glycolysis was increased in order to compensate energy needs of the cell. However, no mitochondrial deficit was observed in primary neuronal, astrocytic and fibroblast cultures. Immortalization of the cell lines mimics the uncontrolled proliferation of cancer cells, which may indicate a contribution of PSs to cancer-related cellular processes. Nevertheless, these results question the contribution of PSs in the bioenergetic aspect of AD and raise questions about these widely used lines.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 202