Progress in understanding mitochondrial calcium uniporter complex‐mediated calcium signalling: A potential target for cancer treatment

Abstract

Due to its Ca 2+ buffering capacity, the mitochondrion is one of the most important intracellular organelles in regulating Ca 2+ dynamic oscillation. Mitochondrial calcium uniporter (MCU) is the primary mediator of Ca 2+ influx into mitochondria, manipulating cell energy metabolism, ROS production, and programmed cell death, all of which are critical for carcinogenesis. The understanding of the uniporter complex was significantly boosted by recent groundbreaking discoveries that identified the uniporter pore-forming subunit MCU and its regulatory molecules, including MCU-dominant negative β subunit (MCUb), essential MCU regulator (EMRE), MCU regulator 1 (MCUR1), mitochondrial calcium uptake (MICU) 1, MICU2, and MICU3. These provide the means and molecular platform to investigate MCU complex (uniplex)-mediated impaired Ca 2+ signalling in physiology and pathology. This review aims to summarize the progress of the understanding regulatory mechanisms of uniplex, roles of uniplex-mediated Ca 2+ signalling in cancer, and potential pharmacological inhibitors of MCU.

Sphingosine 1-phosphate protects against radiation-induced ovarian injury in female rats—impact on mitochondrial-related genes

“…Mitochondria are one of the most important intracellular organelles for the regulation of Ca 2+ homeostasis due to their strong Ca 2+ buffering capacity. The regulation of mitochondrial Ca 2+ is crucial for biological functions and cell signal transduction [21]. The mitochondrial calcium unidirectional transport complex plays an essential role in mitochondrial calcium homeostasis.…”

“…Abnormal mitochondrial calcium homeostasis can accelerate the production of reactive oxygen species (ROS). Therefore, a positive feedback regulatory loop is formed among the mitochondrial calcium influx-respiratory chain-proton gradient across the mitochondrial inner membrane, and the three are closely related, thus exacerbating the damage effects [21]. Therefore, the downregulation of UQCRH, MICU2 and GPX4 genes after radiation may have a deeper connection and synergistic effect on the damage to mitochondrial function.…”

Mitochondrial Calcium Regulation of Redox Signaling in Cancer

“…The discovery of MCU and its regulatory proteins opens a new era in the study of MCU-mediated mitochondrial Ca 2+ homeostasis in cancer. Currently, the available candidate agents targeting MCU or its regulators in cancer chemotherapy are still burgeoning [141,142], and much progress needs to be made in order to test their efficacy as anti-cancer agents to improve clinical chemotherapeutic outcomes in cancer patients. As illustrated in Table 2, the use of these agents in cancer studies has been limited, and the information garnered from this work is still in its infancy.…”

Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins

“…The complex consists of several subunits, including transmembrane core components and regulatory subunits that are associated with the membrane. The core components of the MCU multi-protein complex (see Box 2 for details) are comprised of: (a) core protein components: Mitochondrial Ca 2+ Uniporter (MCU), a MCU dominant negative beta subunit (MCUb), and Essential MCU REgulator (EMRE); and (b) membrane associated regulatory components: mitochondrial Ca 2+ uptake protein 1–3 (MICU1–3) and Mitochondrial Ca 2+ Uniporter Regulator 1 (MCUR1) [ 12 , 13 , 23 , 42 , 47 , 68 , 69 , 70 , 71 , 72 ]. Solute Carrier 25A23 (SLC25A23)) was initially identified as an essential component of MCU, however, it is currently under debate whether SLC25A23 is an component of MCU or whether it influences MCU indirectly [ 13 , 42 , 73 ].…”

“…MCUb (MCU dominant negative beta subunit, formerly known as CCDC109b, 40 kDa) is a core component of the MCU multi-protein complex encoded by the MCUb gene, and is present in all vertebrates [ 71 , 72 , 74 ]. It exhibits a 50% homology with MCU; however, MCU and MCUb demonstrate diverse expression profiles in different tissues.…”