MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

Abstract

The versatility and universality of Ca2+ as intracellular messenger is guaranteed by the compartmentalization of changes in [Ca2+]. In this context, mitochondrial Ca2+ plays a central role, by regulating both specific organelle functions and global cellular events. This versatility is also guaranteed by a cell type-specific Ca2+ signaling toolkit controlling specific cellular functions. Accordingly, mitochondrial Ca2+ uptake is mediated by a multimolecular structure, the MCU complex, which differs among various tissues. Its activity is indeed controlled by different components that cooperate to modulate specific channeling properties. We here investigate the role of MICU3, an EF-hand containing protein expressed at high levels especially in brain. We show that MICU3 forms a disulfide bond-mediated dimer with MICU1, but not with MICU2, and it acts as enhancer of MCU-dependent mitochondrial Ca2+ uptake. Silencing of MICU3 in primary cortical neurons impairs Ca2+ signals elicited by synaptic activity, thus suggesting a specific role in regulating neuronal function.

The crystal structure of MICU 2 provides insight into Ca 2+ binding and MICU 1‐ MICU 2 heterodimer formation

“…Recently, two articles reported that MICU1 can directly interact with the conserved D-ring of MCU to regulate the Ca 2+ uptake [24,25]. MICU1-MICU2 complex has been shown to exert regulatory function for MCU's activity [7,17,23,[26][27][28][29], although how MICU1 interacts with MICU2 to regulate Ca 2+ uptake is not clear.…”

“…Furthermore, it has been suggested that disulfide formation between MICU2 and MICU1 which is facilitated by oxidoreductase Mia40 stabilizes the heterodimer in physiological condition [23]. Distinct from MICU1, only MICU1-MICU2 heterodimer but not MICU2 alone was detected in cells [18,23,26,28].…”

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

“…MICU1 is broadly expressed in most of the tissues; MICU2 is expressed primarily in visceral organs, whereas MICU3 is mostly in skeletal muscles and the CNS (Pagliarini et al, 2008;Plovanich et al, 2013 (Payne, Hoff, Roskowski, & Foskett, 2017). MICU3 also has the targeting sequence to support its mitochondrial localization, and has been shown to localize in mitochondria (Patron et al, 2019;Plovanich et al, 2013), although it does not achieve the score needed to be listed in MitoCarta (Patron et al, 2019;Plovanich et al, 2013). MICU2 has a conserved domain architecture like MICU1, and is found to reside within mitochondria with high-content microscopy and MitoCarta (an inventory of human and mouse genes encoding proteins with strong support of mitochondrial localization).…”

“…However, once cytoplasmic Ca 2+ ([Ca 2+ ] c ) is rapidly elevated (>300-500 nM), the MCU will be activated promptly and transport Ca 2+ into mitochondria, even against the Ca 2+ concentration gradient (Chaudhuri et al, 2013;Kamer, Grabarek, & Mootha, 2017;Marchi & Pinton, 2014). With two TMDs, N-and C-terminals of MCUR1 face the mitochondria inner membrane space Mitochondrion manipulate its activities (Lambert, Luongo, Shah, & Elrod, 2016;Patron, Granatiero, Espino, Rizzuto, & De Stefani, 2019;Perocchi et al, 2010;Plovanich et al, 2013;Sancak et al, 2013). The MCU and its regulatory molecules, including the MCU-dominant negative beta subunit (MCUb), essential MCU regulator (EMRE), MCU regulator 1 (MCUR1), mitochondrial calcium uptake (MICU) 1, MICU2, and MICU3, form a large complex to FIGURE 1 Uniplex components and uniplexmediated mitochondrial Ca 2+ uptake in the global Ca 2+ dynamic.…”

“…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 Mitochondrion manipulate its activities (Lambert, Luongo, Shah, & Elrod, 2016;Patron, Granatiero, Espino, Rizzuto, & De Stefani, 2019;Perocchi et al, 2010;Plovanich et al, 2013;Sancak et al, 2013).…”