UPR(mt) and coordinated UPR(ER) in type 2 diabetes

The mitochondrial unfolded protein response (UPR(mt)) is a molecular mechanism that maintains mitochondrial proteostasis under stress and is closely related to various metabolic diseases, such as type 2 diabetes (T2D). Similarly, the unfolded protein response of the endoplasmic reticulum (UPR(ER)) is responsible for maintaining proteomic stability in the endoplasmic reticulum (ER). Since the mitochondria and endoplasmic reticulum are the primary centers of energy metabolism and protein synthesis in cells, respectively, a synergistic mechanism must exist between UPR(mt) and UPR(ER) to cooperatively resist stresses such as hyperglycemia in T2D. Increasing evidence suggests that the protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK) signaling pathway is likely an important node for coordinating UPR(mt) and UPR(ER). The PERK pathway is activated in both UPR(mt) and UPR(ER), and its downstream molecules perform important functions. In this review, we discuss the mechanisms of UPR(mt), UPR(ER) and their crosstalk in T2D.