Presenilin 2 Modulates Endoplasmic Reticulum-Mitochondria Coupling by Tuning the Antagonistic Effect of Mitofusin 2

Communication between organelles plays key roles in cell biology. In particular, physical and functional coupling of the endoplasmic reticulum (ER) and mitochondria is crucial for regulation of various physiological and pathophysiological processes. Here, we demonstrate that Presenilin 2 (PS2), mutations in which underlie familial Alzheimer’s disease (FAD), promotes ER-mitochondria coupling only in the presence of mitofusin 2 (Mfn2). PS2 is not necessary for the antagonistic effect of Mfn2 on organelle coupling, although its abundance can tune it. The two proteins physically interact, whereas their homologues Mfn1 and PS1 are dispensable for this interplay. Moreover, PS2 mutants associated with FAD are more effective than the wild-type form in modulating ER-mitochondria tethering because their binding to Mfn2 in mitochondria-associated membranes is favored. We propose a revised model for ER-mitochondria interaction to account for these findings and discuss possible implications for FAD pathogenesis. [Display omitted] •Presenilin 2 (PS2) needs Mitofusin 2 (Mfn2) to modulate ER-mitochondria coupling•PS2 interacts with Mfn2 and blocks its negative activity on organelle tethering•PS1 and Mfn1 are dispensable for this molecular interplay•Alzheimer’s disease PS2 mutants bind Mfn2 more efficiently at MAMs Filadi et al. find that the familial Alzheimer’s disease (FAD)-related protein Presenilin 2, enriched at mitochondria-associated membranes, positively modulates endoplasmic reticulum (ER)-mitochondria coupling by binding to Mitofusin 2 and blocking its negative effects on organelle tethering.