As newly found cellular stress response, the mitochondrial unfolded protein response (UPR^mt) is associated with the pathological process of aging, cancer and neurodegenerative diseases. To maintain mitochondrial protein homeostasis, cell will inspire UPR^mt program by activating the transcription of mitochondrial chaperones and proteases encoded by nuclear DNA. Exploring the mechanisms of UPRmt is essential for understanding the pathological process of aging and mitochondria-related diseases. In this review, we focus on various inducers of UPR^mt, the different mechanisms of UPR^mt, the regulatory factors, and relationship with aging, immunity and other diseases in C. elegans and mammalian cells to provide new theoretical basis and therapeutic target for these diseases.