Structure of intact human MCU supercomplex with the auxiliary MICU subunits

Abstract

Structure of intact human MCU supercomplex with the auxiliary MICU subunits Dear Editor, Mitochondrial Ca 2+ homeostasis regulates energy production, cell division, and cell death. The basic properties of mitochondrial Ca 2+ uptake have been firmly established. The Ca 2+ influx is mediated by MCU, driven by membrane potential and using a uniporter mechanism (Vasington and Murphy, 1962). Patch-clamp analysis of MCU currents demonstrated that MCU is a channel with exceptionally high Ca 2+ selectivity (Kirichok et al., 2004). Even in the absence of structural data on the MCU complex, mitochondrial Ca 2+ uptake and its regulation in mammals has been assumed to rely on a complex comprising MCU, EMRE, MICU1, and MICU2 (De Stefani et al., 2016). Previous models generally believe that MICU1 and MICU2 form a cap to occlude the MCU channel in low [Ca 2+ ] condition, and when [Ca 2+ ] is elevated, through conformational changes of the EF hands in these two regulators, they will depart from the MCU/EMRE pore to allow Ca 2+ permeation (Phillips et al., 2019).

From the Identification to the Dissection of the Physiological Role of the Mitochondrial Calcium Uniporter: An Ongoing Story

“…The gating mechanism by which MICU1 regulates the uniporter activity via the conformational change triggered by Ca 2+ was finally unveiled [ 44 ]. Furthermore, the precise description of the molecular interactions between MCU-EMRE-MICU1-MICU2 in the human MCU supercomplex (MEMMS) has been also obtained [ 54 ] ( Figure 2 ). Indeed, MEMMS appears as a 480 kDa integral unit where EMRE coordinates the matrix gate of the MCU channel and MICU proteins interact with the C -terminus of EMRE in the IMS thus enhancing Ca 2+ influx through the MCU pore in high [Ca 2+ ] conditions [ 54 ] ( Figure 3 ).…”

Structure and Reconstitution of an MCU–EMRE Mitochondrial Ca2+ Uniporter Complex

“…In 2019, Wang et al presented a cryo-EM structure of human MCU in complex with EMRE [21]. An additional structure of a hMCU-EMRE complex is available in preprint form [24]. The transmembrane regions of the fungal and human MCU structures are similar, which indicates that the architecture of the pore is structurally conserved among different clades of life despite differences in regulation and the metazoan channel's dependence on EMRE.…”

“…The X-ray and cryo-EM structures show that the channel is formed from a tetrameric assembly of MCU subunits [16][17][18][19]21]. Intriguingly, the cryo-EM analysis of the hMCU-EMRE complexes revealed that a portion of the channels in the purified sample formed dimers comprising a complex of two intact tetrameric channels adjacent to one another [21,24]. The N-terminal domains (NTDs) of human MCU mediate dimerization [21,24].…”

“…Intriguingly, the cryo-EM analysis of the hMCU-EMRE complexes revealed that a portion of the channels in the purified sample formed dimers comprising a complex of two intact tetrameric channels adjacent to one another [21,24]. The N-terminal domains (NTDs) of human MCU mediate dimerization [21,24]. In addition to channel dimers, isolated channels were observed in the most recent structural study [24], which suggests that channel oligomerization is dynamic.…”

“…The N-terminal domains (NTDs) of human MCU mediate dimerization [21,24]. In addition to channel dimers, isolated channels were observed in the most recent structural study [24], which suggests that channel oligomerization is dynamic. Dimer formation seems to be dependent upon EMRE to some extent because dimerization was not observed in a cryo-EM sample without it [21].…”