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Mfn2 modulates the UPR and mitochondrial function via repression of PERK

Juan Pablo Muñoz, Saška Ivanova, Jana Sánchez‐Wandelmer, Paula Martínez‐Cristóbal, Eduard Noguera, Ana Sancho, Angels Díaz‐Ramos, María Isabel Hernández‐Alvarez, David Sebastián, Caroline Mauvezin, Manuel Palacín, Antonio Zorzano

Author Affiliations

  1. Juan Pablo Muñoz1,2,3,
  2. Saška Ivanova1,2,3,
  3. Jana Sánchez‐Wandelmer1,2,3,
  4. Paula Martínez‐Cristóbal1,2,3,
  5. Eduard Noguera1,2,3,
  6. Ana Sancho1,2,3,
  7. Angels Díaz‐Ramos1,2,3,
  8. María Isabel Hernández‐Alvarez1,2,3,
  9. David Sebastián1,2,3,
  10. Caroline Mauvezin1,2,3,
  11. Manuel Palacín1,2 and
  12. Antonio Zorzano*,1,2,3
  1. 1 Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
  2. 2 Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
  3. 3 CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
  1. *Corresponding author. Institute for Research in Biomedicine (IRB Barcelona), C/Baldiri Reixac 10, 08028 Barcelona, Spain. Tel.:+34 93 4037197; Fax:+34 93 4034717; E-mail: antonio.zorzano{at}
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Mitofusin 2 (Mfn2) is a key protein in mitochondrial fusion and it participates in the bridging of mitochondria to the endoplasmic reticulum (ER). Recent data indicate that Mfn2 ablation leads to ER stress. Here we report on the mechanisms by which Mfn2 modulates cellular responses to ER stress. Induction of ER stress in Mfn2‐deficient cells caused massive ER expansion and excessive activation of all three Unfolded Protein Response (UPR) branches (PERK, XBP‐1, and ATF6). In spite of an enhanced UPR, these cells showed reduced activation of apoptosis and autophagy during ER stress. Silencing of PERK increased the apoptosis of Mfn2‐ablated cells in response to ER stress. XBP‐1 loss‐of‐function ameliorated autophagic activity of these cells upon ER stress. Mfn2 physically interacts with PERK, and Mfn2‐ablated cells showed sustained activation of this protein kinase under basal conditions. Unexpectedly, PERK silencing in these cells reduced ROS production, normalized mitochondrial calcium, and improved mitochondrial morphology. In summary, our data indicate that Mfn2 is an upstream modulator of PERK. Furthermore, Mfn2 loss‐of‐function reveals that PERK is a key regulator of mitochondrial morphology and function.

  • Received September 25, 2012.
  • Accepted July 3, 2013.
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