Mfn2 modulates the UPR and mitochondrial function via repression of PERK.
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.
Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
Juan Pablo
JP
Muñoz
Saška
S
Ivanova
Jana
J
Sánchez-Wandelmer
Paula
P
Martínez-Cristóbal
Eduard
E
Noguera
Ana
A
Sancho
Angels
A
Díaz-Ramos
María Isabel
MI
Hernández-Alvarez
David
D
Sebastián
Caroline
C
Mauvezin
Manuel
M
Palacín
Antonio
A
Zorzano
D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology*; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C497112:Atf6 protein, mouse; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C486556:Ern2 protein, mouse; C488751:Mfn2 protein, mouse