The PERK Arm of the Unfolded Protein Response Regulates Mitochondrial Morphology during Acute Endoplasmic Reticulum Stress

Summary: Endoplasmic reticulum (ER) stress is transmitted to mitochondria and is associated with pathologic mitochondrial dysfunction in diverse diseases. The PERK arm of the unfolded protein response (UPR) protects mitochondria during ER stress through the transcriptional and translational remodeling of mitochondrial molecular quality control pathways. Here, we show that ER stress also induces dynamic remodeling of mitochondrial morphology by promoting protective stress-induced mitochondrial hyperfusion (SIMH). ER-stress-associated SIMH is regulated by the PERK arm of the UPR and activated by eIF2α phosphorylation-dependent translation attenuation. We show that PERK-regulated SIMH is a protective mechanism to prevent pathologic mitochondrial fragmentation and promote mitochondrial metabolism in response to ER stress. These results identify PERK-dependent SIMH as a protective stress-responsive mechanism that regulates mitochondrial morphology during ER stress. Furthermore, our results show that PERK integrates transcriptional and translational signaling to coordinate mitochondrial molecular and organellar quality control in response to pathologic ER insults. : Endoplasmic reticulum (ER) stress can be transmitted to mitochondria and induce pathologic mitochondrial dysfunction in association with diverse diseases. Here, Lebeau et al. show that the PERK arm of the unfolded protein response protects mitochondria during ER stress by promoting stress-induced mitochondrial hyperfusion. Keywords: PERK, eIF2α phosphorylation, endoplasmic reticulum stress, unfolded protein response, mitochondrial elongation, mitochondrial proteostasis, stress-induced mitochondrial hyperfusio