Insight into the mitochondrial unfolded protein response and cancer: opportunities and challenges

The mitochondrial unfolded protein response (UPR^mt) is an evolutionarily conserved protective transcriptional response that maintains mitochondrial proteostasis by inducing the expression of mitochondrial chaperones and proteases in response to various stresses. The UPR^mt-mediated transcriptional program requires the participation of various upstream signaling pathways and molecules. The factors regulating the UPR^mt in Caenorhabditis elegans (C. elegans) and mammals are both similar and different. Cancer cells, as malignant cells with uncontrolled proliferation, are exposed to various challenges from endogenous and exogenous stresses. Therefore, in cancer cells, the UPR^mt is hijacked and exploited for the repair of mitochondria and the promotion of tumor growth, invasion and metastasis. In this review, we systematically introduce the inducers of UPR^mt, the biological processes in which UPR^mt participates, the mechanisms regulating the UPR^mt in C. elegans and mammals, cross-tissue signal transduction of the UPR^mt and the roles of the UPR^mt in promoting cancer initiation and progression. Disrupting proteostasis in cancer cells by targeting UPR^mt constitutes a novel anticancer therapeutic strategy.