Figure 2.

ER and the mitochondria function together as sensors of nutrient excess and integrators of the response to metabolic stress. Reactive oxygen species (ROS) are free radicals that are generated as a by-product of cellular metabolism from FA and glucose in the mitochondria. FA enhance MAM; thus, excessive cytoplasmic calcium enters in mitochondria and ER, triggering changes in mitochondrial pH and ROS production. This alters mitochondrial membrane potential and opens pores, thus releasing cytochrome c. Several calcium-dependent proteins and kinases are then activated, triggering apoptosis. ROS perturb the redox status of ER lumen and thus inhibit protein folding. The ER-associated protein NADPH oxidase 4 (NOX4) is implicated in ROS generation during disulfide bond formation for proper protein folding. Excess ROS cause oxidative stress, which induces the 3 branches of the UPR. The result of the UPR activation is inflammation and, upon sustained and/or intense stress, apoptosis. FA also disrupt SERCA activity and perturb ER calcium homeostasis. The mTORC1 complex is an important sensor of bioenergetic status and nutrient excess, and induces ER stress by unclear mechanisms. PERK-mediated activation of ATF4 induces NRF2, a transcription factor responsible for antioxidant cell response. Abbreviations: cyt c, cytochrome c (cyt c); Ox. stress, oxidative stress (Ox. Stress); MAM, mitochondria-associated membranes (MAM); mTORC1, mammalian target of rapamycin complex 1 (mTORC1); NOX4, NADPH oxidase 4 (NOX4); ROS, Reactive oxygen species (ROS); SERCA, sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA). Sharp arrows, activators; bar-ended arrows, inhibitors.