Abstract：
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.
摘要：
与实体瘤癌症相关的恶性程度增加和可治疗性差通常归因于线粒体钙(Ca2+)失调。线粒体Ca2+单向转运复合物(mtCU)是线粒体基质中Ca2+摄取的主要模式。mtCU的主要成分是成孔线粒体Ca2+单转体(MCU)亚基,MCU显性负β（MCUb）亚基，必需的MCU调节因子（EMRE）和守门线粒体Ca2摄取1和2（MICU1和MICU2）蛋白。在这次审查中,我们描述了实体瘤癌症类型中mtCU介导的线粒体Ca2+失调，发现在结直肠癌中观察到的mtCU活性增强，乳腺癌,口腔鳞状细胞癌，胰腺癌,肝细胞癌和胚胎性横纹肌肉瘤。相比之下,mtCU活性降低与黑色素瘤有关，而胶质母细胞瘤中mtCU失调的性质仍不清楚。此外，我们表明，许多与癌症相关的多态性可能会改变孔形成MCU和MCUb亚基上的磷酸化位点，哪个集群位于与EMRE的接口处。我们重点介绍了MCU和MCUb的下游/上游生物分子调节剂，它们可以改变mtCU介导的线粒体Ca2+摄取，并可以用作生物标志物或帮助开发新的癌症疗法。此外,我们概述了目前mtCU的小分子抑制剂，它们与关键Asp-Ile-Met-Glu基序的Asp残基相互作用或通过其他变构调节机制阻断Ca2+渗透。最后,我们描述了MCU和MCUb介导的microRNAs与线粒体Ca2+摄取之间的关系,这在癌症新治疗方法的发现中应该考虑。
