Dataset Information

Mfn2 modulates the UPR and mitochondrial function via repression of PERK.

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.

SUBMITTER: Munoz JP

PROVIDER: S-EPMC3770335 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Mfn2 modulates the UPR and mitochondrial function via repression of PERK.

Muñoz Juan Pablo JP Ivanova Saška S Sánchez-Wandelmer Jana J Martínez-Cristóbal Paula P Noguera Eduard E Sancho Ana A Díaz-Ramos Angels A Hernández-Alvarez María Isabel MI Sebastián David D Mauvezin Caroline C Palacín Manuel M Zorzano Antonio A

The EMBO journal 20130806 17

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 ...[more]

PMID: 23921556

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Project description:BackgroundAutophagy and ER stress are involved in maintaining some well-orchestrated mechanisms aimed at either restoring cellular homeostasis or performing cell death. Autophagy is a well-defined process which governs overall cellular stress outcomes. Selective degradation of the ER mediated by autophagy occurs through a specific type of autophagy called ER-phagy, which ensures ER protein homeostasis.MethodsImmunoblotting and RT-PCR were used to evaluate the expression of ATG5 and ATG7 in chondrocyte. Western blotting, Flow cytometry,immunofluorescence cell staining and confocal microscope were used to examine the effect of ATG5 and ATG7 on autophagy, ER stress, cell apoptosis and cell proliferation. Transmission electron microscope and confocal microscope were performed to visualize the autophagy flux and autolysosome formation. The role of ATG5 and ATG7 overexpression on the PERK pathway inhibitor were detected by immunoblotting and treatment with inhibitors.ResultsIn current study, we demonstrated that Tm-induced ER stress can activate autophagy while Rapamycin-induced autophagy can inhibit ER stress in chondrocyte. Autophagy related protein ATG5 or ATG7 can promote autophagy and inhibit ER stress individually, and their combined effect can further improve the autophagy enhancement and the ER stress repression. Moreover, ATG5, ATG7 and ATG5 + ATG7 lead cells into more S phase, increase the number of S phase and inhibit apoptosis as well. ATG5, ATG7 and ATG5 + ATG7 regulate autophagy, ER stress, apoptosis and cell cycle through PERK signaling, a vital UPR branch pathway.ConclusionsATG5 and ATG7 connect autophagy with ER stress through PERK signaling. The protective effect of ATG5/7 overexpression on chondrocyte survival relys on PERK signaling. The effect of siPERK and siNrf2 on the cytoprotective effect of ATG5/7 are of synergism, while the effect of siPERK and siATF4 are of antagonism. PERK signal may be the pivot for autophagy, ER homeostasis and ER-phagy in chondrocyte.

Dataset Information

Mfn2 modulates the UPR and mitochondrial function via repression of PERK.

Publications

Mfn2 modulates the UPR and mitochondrial function via repression of PERK.

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