Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid ?-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 ?-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 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 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.

SUBMITTER: Leal NS 

PROVIDER: S-EPMC4988279 | biostudies-other | 2016 Sep

REPOSITORIES: biostudies-other