Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex

Abstract

Mitochondrial Ca2+ uptake, a process crucial for bioenergetics and Ca2+ signaling, is catalyzed by the mitochondrial calcium uniporter. The uniporter is a multi-subunit Ca2+-activated Ca2+ channel, with the Ca2+ pore formed by the MCU protein and Ca2+-dependent activation mediated by MICU subunits. Recently, a mitochondrial inner membrane protein EMRE was identified as a uniporter subunit absolutely required for Ca2+ permeation. However, the molecular mechanism and regulatory purpose of EMRE remain largely unexplored. Here, we determine the transmembrane orientation of EMRE, and show that its known MCU-activating function is mediated by the interaction of transmembrane helices from both proteins. We also reveal a second function of EMRE: to maintain tight MICU regulation of the MCU pore, a role that requires EMRE to bind MICU1 using its conserved C-terminal polyaspartate tail. This dual functionality of EMRE ensures that all transport-competent uniporters are tightly regulated, responding appropriately to a dynamic intracellular Ca2+ landscape.DOI: http://dx.doi.org/10.7554/eLife.15545.001

Structural Insights into Mitochondrial Calcium Uniporter Regulation by Divalent Cations

“…Thus, while a fraction of MCU molecules could be loaded with Mg 2+ under physiological conditions, the level of saturation and MCU inhibition may change dependent on the metabolic state of the cell. With the known role of MICU1 as a gatekeeper of MCU in the resting state (Csordas et al, 2013; Mallilankaraman et al, 2012b; Tsai et al, 2016), it is conceivable that both MICU proteins and divalent cations modulate MCU activity. Indeed, it has long been known that mitochondrial Ca 2+ uptake can be inhibited by Mg 2+ (Favaron and Bernardi, 1985; Prentki et al, 1983), and inhibition can occur after physiologically-relevant elevations in cytosolic Mg 2+ (Szanda et al, 2009).…”

MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

“…MCU represents the Ca 2+ -permeant pore forming subunit15, while MCUb acts as an endogenous dominant-negative isoform by inserting in the MCU multimer and inhibiting its Ca 2+ channeling activity17. EMRE is a small membrane protein necessary to form a functional MCU complex in vivo, at least in vertebrates18,21,22. Finally, MCUR1 was originally reported to be a regulator of the MCU complex23,24, although it was also proposed to function as a COX assembly factor, opening the possibility that the defect ascribed to modulation of MCU channel activity can be secondary to the respiratory chain defect25.…”

MICU2 Restricts Spatial Crosstalk between InsP 3 R and MCU Channels by Regulating Threshold and Gain of MICU1-Mediated Inhibition and Activation of MCU

“…MCU constitutes the pore-forming subunit (Baughman et al, 2011; De Stefani et al, 2011), and interacts with several proteins to regulate its activity, including Mitochondrial Calcium Uptake protein 1 (MICU1) (Perocchi et al, 2010), its paralogs MICU2 and MICU3 (Plovanich et al, 2013), Mitochondrial Calcium Uniporter Regulator 1 (MCUR1) (Mallilankaraman et al, 2012), and Essential MCU Regulator (EMRE) (Sancak et al, 2013). EMRE is a membrane protein that interacts with and is essential for MCU-channel activity in mammalian cells (Sancak et al, 2013) and may tether MICU1 to the channel complex (Tsai et al, 2016). In humans, MICU1 and MICU2 are widely expressed, whereas MICU3 appears to be largely restricted to the central nervous system (Plovanich et al, 2013).…”