Mitochondria at the interface between danger signaling and metabolism: role of unfolded protein responses in chronic inflammation

Inflammatory bowel diseases (IBDs), like many other chronic diseases, feature multiple cellular stress responses including endoplasmic reticulum (ER) unfolded protein response (UPR). Maintaining protein homeostasis is indispensable for cell survival and, consequently, distinct signaling pathways have evolved to transmit organelle stress. While the ER UPR, aiming to restore ER homeostasis after challenges to ER function, has been extensively studied in the context of chronic diseases, only recently the related mitochondrial UPR (mtUPR), induced by disturbances of mitochondrial proteostasis, has drawn some attention. ER and mitochondria are in close contact and interact physically and functionally. Accumulating data have placed mitochondria at the center of diverse cellular functions and suggest mitochondria as integrators of signaling pathways such as autophagy and inflammation. Consequently, it is likely that mitochondrial stress and ER stress cannot be regarded separately and that mitochondrial stress, as well as ER stress, participates in the pathology of IBD. Protein homeostasis is particularly sensitive toward infections, oxidative stress, and energy deficiency. Thus, environmental disturbances impacting organelle function lead to the concerted activation of distinct UPRs. The metabolic status might therefore serve as an innate mechanism to sense the epithelial environment, including luminal-derived and host-derived factors. This review highlights mtUPR and its interrelation with ER UPR, focuses on recent studies identifying mitochondria as integrators of cellular danger signaling, and, furthermore, illustrates the importance ER UPR and mitochondrial dysfunction in IBD.