Open AccessMitofusin‐2 knockdown increases ER –mitochondria contact and decreases amyloid β‐peptide production
Author(s) -
Leal Nuno Santos,
Schreiner Bernadette,
Pinho Catarina Moreira,
Filadi Riccardo,
Wiehager Birgitta,
Karlström Helena,
Pizzo Paola,
Ankarcrona Maria
Publication year - 2016
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12863
Subject(s) - mitochondrion , endoplasmic reticulum , mfn2 , microbiology and biotechnology , organelle , unfolded protein response , gene knockdown , chemistry , amyloid precursor protein , mitochondrial fusion , biology , biochemistry , apoptosis , alzheimer's disease , medicine , mitochondrial dna , gene , disease
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 si RNA 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 Aβ 40 and Aβ 42 . 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 si RNA 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.