Mfn2 modulates the UPR and mitochondrial function via repression of PERK

• Published in: The EMBO journal 2013-08, Vol.32 (17), p.2348-2361
• Main Authors: Muñoz, Juan Pablo, Ivanova, Saška, Sánchez-Wandelmer, Jana, Martínez-Cristóbal, Paula, Noguera, Eduard, Sancho, Ana, Díaz-Ramos, Angels, Hernández-Alvarez, María Isabel, Sebastián, David, Mauvezin, Caroline, Palacín, Manuel, Zorzano, Antonio
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 6 - genetics; Activating Transcription Factor 6 - metabolism; Animals; Apoptosis - genetics; Autophagy - genetics; Calcium; cell death and autophagy; cell metabolism; Cells, Cultured; Cellular biology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; EMBO20; EMBO37; Endoplasmic Reticulum Stress; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Gene expression; Gene Knockout Techniques; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; Humans; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; Reactive Oxygen Species - metabolism; Regulatory Factor X Transcription Factors; Signal transduction; Stress; Stress response; Transcription Factors - genetics; Transcription Factors - metabolism; Unfolded Protein Response - physiology; Upstream; X-Box Binding Protein 1
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2013.168

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. Mitochondrial–ER bridging protein mitofusin 2 (Mfn2) orchestrates mitochondrial metabolism and the UPR by suppressing PERK.