Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production
| Autor: | Catarina Moreira Pinho, Riccardo Filadi, Paola Pizzo, Helena Karlström, Maria Ankarcrona, Nuno Santos Leal, Bernadette Schreiner, Birgitta Wiehager |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Amyloid ER–mitochondria contacts MFN2 Down-Regulation Mitochondrion Biology Endoplasmic Reticulum GTP Phosphohydrolases Mitochondrial Proteins 03 medical and health sciences Adenosine Triphosphate Organelle Extracellular Humans RNA Small Interfering Neprilysin Aβ γ‐secretase Gene knockdown Amyloid beta-Peptides Endoplasmic reticulum Cell Biology Original Articles Alzheimer's disease Cell biology Mitochondria 030104 developmental biology HEK293 Cells Biochemistry Gene Knockdown Techniques Molecular Medicine Calcium Original Article Amyloid Precursor Protein Secretases Mitofusin‐2 |
| Zdroj: | Journal of Cellular and Molecular Medicine |
| ISSN: | 1582-4934 |
| Popis: | 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 Ca2+ 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 Ca2+ 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. |
| Databáze: | OpenAIRE |
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