Loosening ER–Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain

Abstract

Presenilin 2 (PS2), one of the three proteins in which mutations are linked to familial Alzheimer’s disease (FAD), exerts different functions within the cell independently of being part of the γ-secretase complex, thus unrelated to toxic amyloid peptide formation. In particular, its enrichment in endoplasmic reticulum (ER) membrane domains close to mitochondria (i.e., mitochondria-associated membranes, MAM) enables PS2 to modulate multiple processes taking place on these signaling hubs, such as Ca2+ handling and lipid synthesis. Importantly, upregulated MAM function appears to be critical in AD pathogenesis. We previously showed that FAD-PS2 mutants reinforce ER–mitochondria tethering, by interfering with the activity of mitofusin 2, favoring their Ca2+ crosstalk. Here, we deepened the molecular mechanism underlying PS2 activity on ER–mitochondria tethering, identifying its protein loop as an essential domain to mediate the reinforced ER–mitochondria connection in FAD-PS2 models. Moreover, we introduced a novel tool, the PS2 loop domain targeted to the outer mitochondrial membrane, Mit-PS2-LOOP, that is able to counteract the activity of FAD-PS2 on organelle tethering, which possibly helps in recovering the FAD-PS2-associated cellular alterations linked to an increased organelle coupling.

Simultaneous detection of membrane contact dynamics and associated Ca2+signals by reversible chemogenetic reporters

“…Similarly, a higher ER-mitochondria tethering was observed in human fibroblasts from a patient harboring a familial AD mutation in Presenilin 2, compared to those from an age-matched healthy donor ( Fig. 4f ), as previously reported 23,25,26 . Overall, these data demonstrate that the splitFAST-based probes can detect MCS alterations in disease models.…”

Sustained IP3-linked Ca2+ signaling promotes progression of triple negative breast cancer cells by regulating fatty acid metabolism

“…Zoom, laser intensity, HyD gain were kept constant across different conditions for a better comparison. Images were analysed by Fiji (NIH), essentially as described ( Rossini et al, 2021 ). Briefly, LD number, volume and surface was calculated through all stacks by the 3D Objects Counter plugin after imposing a threshold (corresponding to 2× the mean fluorescence intensity of each cell), considering only objects in the range 5–500 pixels.…”

Presenilins and mitochondria—an intriguing link: mini-review

“…Conversely, excessive levels of calcium transferred from the ER to mitochondria-associated ER membranes can give rise to mitochondrial Ca 2+ overload, leading to the decoupling of the oxidative phosphorylation chain and subsequent reduction in ATP production (Kushnireva and Korkotian, 2022). Strikingly, some studies report that mitochondrial Ca 2+ uptake in FAD-linked PS2 mutants is reduced as a result of decreased ER Ca 2+ , causing a blunted increase in cytosolic Ca 2+ after stimulation (Rossini et al, 2021). These effects also depend on the ability of PS2 to partially block SERCA activity and induce hyperactivation of IP3 receptors (Rossini et al, 2021).…”