title: Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production.
abstract: Mitochondria are physically and biochemically in contact with other organelles including the endoplasmic reticulum (ER). Such contacts are formed between mitochondria-associated ER membranes (MAM), specialized subregions of ER, and the outer mitochondrial membrane (OMM). We have previously shown increased expression of MAM-associated proteins and enhanced ER to mitochondria Ca(2+) transfer from ER to mitochondria in Alzheimer's disease (AD) and amyloid β-peptide (Aβ)-related neuronal models. Here, we report that siRNA knockdown of mitofusin-2 (Mfn2), a protein that is involved in the tethering of ER and mitochondria, leads to increased contact between the two organelles. Cells depleted in Mfn2 showed increased Ca(2+) transfer from ER to mitchondria and longer stretches of ER forming contacts with OMM. Interestingly, increased contact resulted in decreased concentrations of intra- and extracellular Aβ40 and Aβ42 . Analysis of γ-secretase protein expression, maturation and activity revealed that the low Aβ concentrations were a result of impaired γ-secretase complex function. Amyloid-β precursor protein (APP), β-site APP-cleaving enzyme 1 and neprilysin expression as well as neprilysin activity were not affected by Mfn2 siRNA treatment. In summary, our data shows that modulation of ER-mitochondria contact affects γ-secretase activity and Aβ generation. Increased ER-mitochondria contact results in lower γ-secretase activity suggesting a new mechanism by which Aβ generation can be controlled.
authors.affiliation: Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nuno Santos
authors.initials: NS
authors.lastname: Leal
authors.affiliation: Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Schreiner
authors.affiliation: Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Catarina Moreira
authors.initials: CM
authors.lastname: Pinho
authors.affiliation: Department of Biomedical Sciences, University of Padua, Padua, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Filadi
authors.affiliation: Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Wiehager
authors.affiliation: Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Karlström
authors.affiliation: Department of Biomedical Sciences, University of Padua, Padua, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Pizzo
authors.affiliation: Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Ankarcrona
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D000255:Adenosine Triphosphate; D053829:Amyloid Precursor Protein Secretases; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; D002118:Calcium
keywords: Alzheimer's disease; Aβ; ER-mitochondria contacts; Mitofusin-2; γ-secretase