title: Presenilin 2 Modulates Endoplasmic Reticulum-Mitochondria Coupling by Tuning the Antagonistic Effect of Mitofusin 2.
abstract: 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.
authors.affiliation: Department of Biomedical Sciences, University of Padua, via U. Bassi 58/B, Padua 35131, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Filadi
authors.affiliation: Department of Biomedical Sciences, University of Padua, via U. Bassi 58/B, Padua 35131, Italy; Department of Biomedical Sciences, Institute of Neuroscience, Italian National Research Council (CNR), via U. Bassi 58/B, Padua 35131, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Greotti
authors.affiliation: Department of Biomedical Sciences, Institute of Protein Biochemistry, Italian National Research Council (CNR), via P. Castellino 111, Naples 80131, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Turacchio
authors.affiliation: Department of Biomedical Sciences, Institute of Protein Biochemistry, Italian National Research Council (CNR), via P. Castellino 111, Naples 80131, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Luini
authors.affiliation: Department of Biomedical Sciences, University of Padua, via U. Bassi 58/B, Padua 35131, Italy; Venetian Institute of Molecular Medicine, via Orus 2, Padua 35131, Italy; Department of Biomedical Sciences, Institute of Neuroscience, Italian National Research Council (CNR), via U. Bassi 58/B, Padua 35131, Italy.
authors.forename: Tullio
authors.initials: T
authors.lastname: Pozzan
authors.affiliation: Department of Biomedical Sciences, University of Padua, via U. Bassi 58/B, Padua 35131, Italy. Electronic address: paola.pizzo@unipd.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Pizzo
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D005347:Fibroblasts / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D053764:Presenilin-1 / Q000378:metabolism; D053766:Presenilin-2 / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D024101:Mitochondrial Proteins; D053764:Presenilin-1; D053766:Presenilin-2; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse; D002118:Calcium