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.

The coming of age of the mitochondria–ER contact: a matter of thickness

“…74 ER stress is well known to a spatial reorganization that correlates with increased ATP levels, oxygen consumption, reductive power and mitochondrial Ca 2+ uptake. 5,8 Strikingly, however, Mfn2-/-MEFs consume less oxygen than controls, 78 unlike what is observed upon ER stress. 5 The administration of chemical chaperones known to alleviate ER stress and the knockdown of the ER stress kinase PERK can partially rescue components of the Mfn2 − / − phenotype, including the reduced oxygen consumption rates; 77,78 taken together these findings suggest that although ablation of Mfn2 causes ER stress, its effect is somewhat different from what happens during 'normal' ER stress, a possibility consistent with an altered quality/type of tethering.…”

“…5,8 Strikingly, however, Mfn2-/-MEFs consume less oxygen than controls, 78 unlike what is observed upon ER stress. 5 The administration of chemical chaperones known to alleviate ER stress and the knockdown of the ER stress kinase PERK can partially rescue components of the Mfn2 − / − phenotype, including the reduced oxygen consumption rates; 77,78 taken together these findings suggest that although ablation of Mfn2 causes ER stress, its effect is somewhat different from what happens during 'normal' ER stress, a possibility consistent with an altered quality/type of tethering. 8 Evidence that during ER stress and metabolic transitions MERCs can change length 4 and thickness (see above) support the concept that MERCs dynamics must have a critical role in the Mfn2 knockout phenotype.…”

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

“…One potential mechanism behind MFN2‐induced autophagy could be linked to its unique localization at the mitochondria‐ER contact site, which is considered as a source for autophagosomal membranes during elongation (Hailey et al., 2010). Absence of mitochondria‐ER interface proteins such as MFN2 and phosphofurin acidic cluster sorting protein 2 (PACS2) prevents proper autophagosome formation in response to autophagic stimuli including starvation (Hamasaki et al., 2013) or ER stress (Muñoz et al., 2013). Moreover, in a recent study, the ER acetylation machinery directly regulates autophagy in the brain (Peng et al., 2016).…”

Structure, function, and regulation of mitofusin‐2 in health and disease

“…Additionally, Mfn2 deficiency led to increased expression of ER chaperone proteins, resulting in amplified ER stress (Ngoh et al, 2012;Sebastian et al, 2012). Moreover, Mfn2 can directly interact with the ER stress-sensing protein kinase RNA-like ER kinase (PERK), and participates in ER stress signalling by modulating PERK-mediated UPR signalling (Munoz et al, 2013). Interestingly, silencing of PERK in mouse embryonic fibroblasts could partially rescue the fragmentation of the mitochondrial network and abnormal mitochondrial calcium content caused by loss of Mfn2 (Munoz et al, 2013).…”