Mfn2 modulates the UPR and mitochondrial function via repression of PERK

Authors

  • Juan Pablo Muñoz,

    1. Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
    2. Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
    3. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
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  • Saška Ivanova,

    1. Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
    2. Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
    3. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
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  • Jana Sánchez-Wandelmer,

    1. Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
    2. Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
    3. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
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  • Paula Martínez-Cristóbal,

    1. Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
    2. Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
    3. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
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  • Eduard Noguera,

    1. Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
    2. Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
    3. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
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  • Ana Sancho,

    1. Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
    2. Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
    3. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
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  • Angels Díaz-Ramos,

    1. Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
    2. Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
    3. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
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  • María Isabel Hernández-Alvarez,

    1. Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
    2. Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
    3. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
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  • David Sebastián,

    1. Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
    2. Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
    3. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
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  • Caroline Mauvezin,

    1. Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
    2. Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
    3. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
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  • Manuel Palacín,

    1. Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
    2. Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
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  • Antonio Zorzano

    Corresponding author
    1. Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
    2. Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
    3. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
    • 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@irbbarcelona.org

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Errata

This article is corrected by:

  1. Errata: Mfn2 modulates the UPR and mitochondrial function via repression of PERK Volume 33, Issue 2, 171, Article first published online: 14 January 2014

Abstract

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.

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