Structural characterization of the mitochondrial Ca2+ uniporter provides insights into Ca2+ uptake and regulation

Abstract

Summary The mitochondrial uniporter is a Ca 2+ -selective ion-conducting channel in the inner mitochondrial membrane that is involved in various cellular processes. The components of this uniporter, including the pore-forming membrane subunit MCU and the modulatory subunits MCUb, EMRE, MICU1, and MICU2, have been identified in recent years. Previously, extensive studies revealed various aspects of uniporter activities and proposed multiple regulatory models of mitochondrial Ca 2+ uptake. Recently, the individual auxiliary components of the uniporter and its holocomplex have been structurally characterized, providing the first insight into the component structures and their spatial relationship within the context of the uniporter. Here, we review recent uniporter structural studies in an attempt to establish an architectural framework, elucidating the mechanism that governs mitochondrial Ca 2+ uptake and regulation, and to address some apparent controversies. This information could facilitate further characterization of mitochondrial Ca 2+ permeation and a better understanding of uniporter-related disease conditions.

MICU1 controls spatial membrane potential gradients and guides Ca2+ fluxes within mitochondrial substructures

“…Phase 1.2. Subsequently, the CJ opens, and Ca 2+ floats into the CL and reaches the mitochondrial matrix via constantly active MCU 38 , 42 in the CM.…”

“…Importantly, the contact with MICU1/2 increases MCU conductance and further introduces MICU1/2-mediated modulation of MCU activity that is crucial to meet the Ca 2+ micro-environment 38 . Further, the V-shaped dimeric structure of MCU, EMRE, MICU1, and MICU2 complexes is favorable for concave membranes, potentially increasing the distribution of MCU out of the convex cristae into the IBM 41 , 42 .…”

“…On the other hand, MICU1 homo and MICU1/MICU2 heterodimers were shown to increase MCU conductance 37 , 38 but do not occlude the MCU channel 38 . Further, three different quaternary structures including MICU1 are known : MICU1 hexamers or oligomers that disassemble Ca 2+ dependent into MICU1 dimers 14 , 39 and the MCU super complex involving MCU, EMRE, MICU1 and MICU2 40 – 42 . MICU1 was shown to potentiate MCU channel activity by direct interaction and MCU is not occluded by MICU1 38 , raising the question of how MICU1 reduces mitochondrial Ca 2+ uptake at low cytosolic Ca 2+ concentrations.…”

The Splicing of the Mitochondrial Calcium Uniporter Genuine Activator MICU1 Is Driven by RBFOX2 Splicing Factor during Myogenic Differentiation

“…As well, the addition of exon 5″ lowers the synergistic activation of MCU when co-expressed with MICU2. As in Mus musculus , the clarification of the structural role of this extra-exon’s insertion is not possible since they are far from the Ca 2+ -binding EF-hand sites, and the numerous crystal structure models of MICU1 did not resolve the loop region that contains the extra-exons [ 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ], indicating that this region is flexible and thus not visible in the electron density map. Therefore, for human MICU1.1 and MICU1.3, we cannot infer on the mechanism by which the extra-exon modifies the affinity of the EF-hand domains and the interaction with MICU2.…”

From passage to inhibition: Uncovering the structural and physiological inhibitory mechanisms of MCUb in mitochondrial calcium regulation

“…The weakened/smaller interface between MCUb and EMRE, shown in both occluded and non‐occluded models, may play a role in the inhibitory mechanism of MCUb, while the enhanced MCUb‐MCUb solvent‐inaccessible interface may promote MCUb‐MCUb assembly. The N‐terminal domain of EMRE contains an extended linker region with a highly conserved PXP motif, thought to stabilize the luminal gate of MCU in an open conformation due to the rigidity of Pro 41,44 . Thus, a tighter MCU interaction (expanded interface) with EMRE could promote the opening of the mtCU luminal gate for Ca 2+ uptake into the matrix, while a weaker MCUb‐EMRE interaction could suppress open probability.…”