ER stress key players PERK and endoplasmic reticulum to nucleus signaling 1 (IRE1) coordinate a response that translates into mitochondrial functional outcomes. Under ER stress or glucose deprivation, phosphorylated PERK engages the activation of eIF2 and ATF4 to transcribe the assembly factor SCAF1, which increases the formation of respiratory supercomplexes and respiration. In turn, stabilized supercomplexes help meet the high request for ATP production and bioenergetic supply from the mitochondria in the absence of glycolysis.206PERK is located at and stabilizes mitochondria-ER contact sites (MERCs).210,211At MERCs, Mfn2 interacts with and acts upstream of PERK to suppress its activation under ER stress, with consequences in ROS production along with mitochondrial respiration, Ca2+overload, and morphology.210Mfn2 also regulates the ATF6 and IRE1 branches of ER stress. IRE1 also represents a major regulator of MERC stability, where it interacts with the inositol triphosphate receptor (InsP3R) to control its location and abundance at MERCs. This interaction facilitates mitochondrial Ca2+elevations to engage metabolic adaptations and ATP production by mitochondria, which can be separated from its role in the unfolded protein response212(see also Quintana-Cabrera and Soriano207).
