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

Increased malignancy and poor treatability associated with solid tumour cancers have commonly been attributed to mitochondrial calcium (Ca2+) dysregulation. The mitochondrial Ca2+ uniporter complex (mtCU) is the predominant mode of Ca2+ uptake into the mitochondrial matrix. The main components of mtCU are the pore-forming mitochondrial Ca2+ uniporter (MCU) subunit, MCU dominant-negative beta (MCUb) subunit, essential MCU regulator (EMRE) and the gatekeeping mitochondrial Ca2+ uptake 1 and 2 (MICU1 and MICU2) proteins. In this review, we describe mtCU-mediated mitochondrial Ca2+ 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 Ca2+ 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 Ca2+ permeation. Finally, we describe the relationship between MCU- and MCUb-mediating microRNAs and mitochondrial Ca2+ uptake that should be considered in the discovery of new treatment approaches for cancer. image Abstract figure legend A solid tumour schematic is shown on the right, highlighting enhanced or suppressed mitochondrial Ca2+ uptake in cancer. Enhanced mitochondrial Ca2+ uniporter complex (mtCU)-mediated Ca2+ uptake (top) is implicated in colorectal cancer, breast cancer, oral squamous cell carcinoma, pancreatic cancer, hepatocellular carcinoma and embryonal rhabdomyosarcoma. Decreased mtCU-mediated mitochondrial Ca2+ uptake (bottom) has been associated with melanoma but remains uncharacterized in glioblastoma. The mitochondrion shown above the tumour depicts enhanced mitochondrial Ca2+ uptake as a result of mtCU channels comprised of 3 x mitochondrial Ca2+ uniporter (MCU) (teal):1 x MCU dominant-negative beta (MCUb) (violet):2 x essential MCU regulator (EMRE) (beige):1 x mitochondrial Ca2+ uptake (MICU)1 (green):1 x MICU2 (pink) subunits, with Ca2+ ions shown in grey. The mitochondrion shown below the tumour depicts suppressed mitochondrial Ca2+ uptake as a result of mtCU channels comprised of 1 x MCU (teal):3 x MCUb (violet) subunits. The dysregulated oncogenic/anti-oncogenic microRNAs (miRNAs), small-molecule inhibitors and post-translational modifications correlated with mtCU-mediated mitochondrial Ca2+ dysfunction are indicated as future avenues and considerations for therapeutic intervention. Created with BioRender.com. image