Mitofusin-2 knockdown increases ER–mitochondria contact and decreases amyloid β-peptide production

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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 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.

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Leal, N. S., Schreiner, B., Pinho, C. M., Filadi, R., Wiehager, B., Karlström, H., … Ankarcrona, M. (2016). Mitofusin-2 knockdown increases ER–mitochondria contact and decreases amyloid β-peptide production. Journal of Cellular and Molecular Medicine, 20(9), 1686–1695. https://doi.org/10.1111/jcmm.12863

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