Hypoxia and Reactive Oxygen Species as Modulators of Endoplasmic Reticulum and Golgi Homeostasis

Significance: Eukaryotic cells execute various functions in subcellular compartments or organelles for which cellular redox homeostasis is of importance. Apart from mitochondria, hypoxia and stress-mediated formation of reactive oxygen species (ROS) were shown to modulate endoplasmic reticulum (ER) and Golgi apparatus (GA) functions. Recent Advances: Research during the last decade has improved our understanding of disulfide bond formation, protein glycosylation and secretion, as well as pH and redox homeostasis in the ER and GA. Thus, oxygen (O2) itself, NADPH oxidase (NOX) formed ROS, and pH changes appear to be of importance and indicate the intricate balance of intercompartmental communication. Critical Issues: Although the interplay between hypoxia, ER stress, and Golgi function is evident, the existence of more than 20 protein disulfide isomerase family members and the relative mild phenotypes of, for example, endoplasmic reticulum oxidoreductin 1 (ERO1)- and NOX4-knockout mice clearly suggest the existence of redundant and alternative pathways, which remain largely elusive. Future Directions: The identification of these pathways and the key players involved in intercompartmental communication needs suitable animal models, genome-wide association, as well as proteomic studies in humans. The results of those studies will be beneficial for the understanding of the etiology of diseases such as type 2 diabetes, Alzheimer's disease, and cancer, which are associated with ROS, protein aggregation, and glycosylation defects.