The mitochondrial calcium uniporter: Balancing tumourigenic and anti‐tumourigenic responses

Abstract Increased malignancy and poor treatability associated with solid tumour cancers have commonly been attributed to mitochondrial calcium (Ca 2+ ) dysregulation. The mitochondrial Ca 2+ uniporter complex (mtCU) is the predominant mode of Ca 2+ uptake into the mitochondrial matrix. The main components of mtCU are the pore‐forming mitochondrial Ca 2+ uniporter (MCU) subunit, MCU dominant‐negative beta (MCUb) subunit, essential MCU regulator (EMRE) and the gatekeeping mitochondrial Ca 2+ uptake 1 and 2 (MICU1 and MICU2) proteins. In this review, we describe mtCU‐mediated mitochondrial Ca 2+ dysregulation in solid tumour cancer types, finding enhanced mtCU activity observed in colorectal cancer, breast cancer, oral squamous cell carcinoma, pancreatic cancer, hepatocellular carcinoma and embryonal rhabdomyosarcoma. By contrast, decreased mtCU activity is associated with melanoma, whereas the nature of mtCU dysregulation remains unclear in glioblastoma. Furthermore, we show that numerous polymorphisms associated with cancer may alter phosphorylation sites on the pore forming MCU and MCUb subunits, which cluster at interfaces with EMRE. We highlight downstream/upstream biomolecular modulators of MCU and MCUb that alter mtCU‐mediated mitochondrial Ca 2+ uptake and may be used as biomarkers or to aid in the development of novel cancer therapeutics. Additionally, we provide an overview of the current small molecule inhibitors of mtCU that interact with the Asp residue of the critical Asp‐Ile‐Met‐Glu motif or through other allosteric regulatory mechanisms to block Ca 2+ permeation. Finally, we describe the relationship between MCU‐ and MCUb‐mediating microRNAs and mitochondrial Ca 2+ uptake that should be considered in the discovery of new treatment approaches for cancer. image