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

摘要

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 -peptide (A)-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 A(40) and A(42). Analysis of -secretase protein expression, maturation and activity revealed that the low A concentrations were a result of impaired -secretase complex function. Amyloid- precursor protein (APP), -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 -secretase activity and A generation. Increased ER-mitochondria contact results in lower -secretase activity suggesting a new mechanism by which A generation can be controlled.