The mitochondrial unfolded protein response (UPR(mt)): shielding against toxicity to mitochondria in cancer

Mitochondria are essential for tumor growth and progression. However, the heavy demand for mitochondrial activity in cancer leads to increased production of mitochondrial reactive oxygen species (mtROS), accumulation of mutations in mitochondrial DNA, and development of mitochondrial dysfunction. If left unchecked, excessive mtROS can damage and unfold proteins in the mitochondria to an extent that becomes lethal to the tumor. Cellular systems have evolved to combat mtROS and alleviate mitochondrial stress through a quality control mechanism called the mitochondrial unfolded protein response (UPR(mt)). The UPR(mt) system is composed of chaperones and proteases, which promote protein folding or eliminate mitochondrial proteins damaged by mtROS, respectively. UPR(mt) is conserved and activated in cancer in response to mitochondrial stress to maintain mitochondrial integrity and support tumor growth. In this review, we discuss how mitochondria become dysfunctional in cancer and highlight the tumor-promoting functions of key components of the UPR(mt).