A bird’s eye view of mitochondrial unfolded protein response in cancer: mechanisms, progression and further applications

Mitochondria are essential organelles that play critical roles in energy metabolism, apoptosis and various cellular processes. Accumulating evidence suggests that mitochondria are also involved in cancer development and progression. The mitochondrial unfolded protein response (UPR^mt) is a complex cellular process that is activated when the protein-folding capacity of the mitochondria is overwhelmed. The core machinery of UPR^mt includes upstream regulatory factors, mitochondrial chaperones and proteases. These components work together to eliminate misfolded proteins, increase protein-folding capacity, and restore mitochondrial function. Recent studies have shown that UPR^mt is dysregulated in various cancers and contributes to tumor initiation, growth, metastasis, and therapeutic resistance. Considering the pivotal role of the UPR^mt in oncogenesis, numerous compounds and synthetic drugs targeting UPR^mt-related components induce cancer cell death and suppress tumor growth. In this review, we comprehensively summarize recent studies on the molecular mechanisms of UPR^mt activation in C. elegans and mammals and elucidate the conceptual framework, functional aspects, and implications of the UPR^mt for cancer therapy. In summary, we paint a developmental landscape of the UPR^mt in different types of cancer and offer valuable insights for the development of novel cancer treatment strategies by targeting the UPR^mt.