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

Abstract

Due to its Ca²⁺ buffering capacity, the mitochondrion is one of the most important intracellular organelles in regulating Ca²⁺ dynamic oscillation. Mitochondrial calcium uniporter (MCU) is the primary mediator of Ca²⁺ 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 Ca²⁺ signalling in physiology and pathology. This review aims to summarize the progress of the understanding regulatory mechanisms of uniplex, roles of uniplex-mediated Ca²⁺ signalling in cancer, and potential pharmacological inhibitors of MCU.

Figure 1

Uniplex components and uniplex‐mediated mitochondrial Ca²⁺ uptake in the global Ca²⁺ dynamic. (a) The dynamics of the intracellular Ca²⁺ oscillation are finely regulated by the mitochondria, SR/ER, lysosome, and channels located on the PM. When Ca²⁺ is transported from the extracellular space or released from intracellular Ca²⁺ stores, mitochondria will move close to the corresponding channel to take up the elevated [Ca²⁺]_c, thus propagate or restrict Ca²⁺ signals to specific cellular domains. Ca²⁺ influx into mitochondria is mainly mediated by the uniplex. (b) Uniplex is composed of the pore‐forming subunit MCU, MCUb, EMRE, MCUR1, MICU1, MICU2, and MICU3. All these molecules localize at the inner mitochondrial membrane. MICU family protein or EMRE molecule contains only single TMD. Both MCU and MCUb contain two TMDs, while both N‐ and C‐terminals face the mitochondrial matrix. With two TMDs, N‐ and C‐terminals of MCUR1 face the mitochondria inner membrane space

Figure 2

Functions of uniplex‐mediated mitochondrial Ca²⁺ uptake. (a) Effect of uniplex‐mediated Ca²⁺ signalling. It buffers the elevated [Ca²⁺]_c, thus transduces or restricts calcium oscillation coded signalling. [Ca²⁺]_m binding to specific proteins directly induces biochemical events, including cell migration, proliferation, survival, ATP production, autophagy, ROS, apoptosis, necrosis, necroptosis, and senescence. Autophagy, [Ca²⁺]_m, and ROS are multifunctional events or factors. (b) Dual roles of [Ca²⁺]_m and mROS. [Ca²⁺]_m and mROS are required for normal cell functions and signalling. Under moderate stress, the increased Ca²⁺ and ROS could enhance the corresponding signalling pathway for adapting to the elevated requirement of ATP, proliferation, and autophagy. Once this promoted adaptive stress is out of control, it may lead to tumourigenesis and cell invasion. However, once [Ca²⁺]_m and mROS accumulation exceed the threshold, death‐related events, such as apoptosis and strong autophagy, will be induced. Manipulation of these processes can regulate the fate

Figure 3

Regulatory mechanisms of uniplex. (a) MCUR1 and MCUb directly bind to MCU, which exerts a positive and dominant negative effect on MCU, respectively. MICU2 is a gatekeeper and MICU3 is an enhancer of MCU, both of which require MICU1‐EMRE heterodimer as a bridge. (b) EMRE directly binds to MICU1 and MCU. At low [Ca²⁺]_c levels, both MICU2 and MICU3 bind to MICU1, and MICU2 inhibits MCU activation. When [Ca²⁺]_c increases and exceeds the Ca²⁺ threshold set by MICU2, the MICU1–MICU2 dimer will dissociate from the uniplex, and MICU2 will lose its inhibitory function; MICU3 enhances MCU activity to transfer Ca²⁺ from the cytosol into the mitochondrial matrix