| 2013 |
MICU2 resides within the mitochondrial uniporter complex (together with MCU and MICU1), cross-stabilizes the protein expression of other complex members in a cell-type dependent manner, and its RNAi silencing in mouse liver additively impairs mitochondrial calcium handling when combined with MICU1 knockdown. |
Co-immunoprecipitation, biochemical fractionation, in vivo RNAi in mouse liver with mitochondrial Ca2+ uptake assays |
PloS one |
High |
23409044
|
| 2014 |
MICU2 sets a cytoplasmic Ca2+ concentration threshold for mitochondrial Ca2+ uptake (gatekeeping); MICU2's activity and physical association with the MCU pore require the presence of MICU1, but MICU1 does not require MICU2. Mutation of MICU2 Ca2+-binding EF-hands causes a dominant-negative loss of Ca2+ uptake. |
CRISPR/Cas9 knockout in HEK-293T cells, EF-hand point mutagenesis, mitochondrial Ca2+ uptake assays, co-immunoprecipitation |
EMBO reports |
High |
24503055
|
| 2015 |
Mia40/CHCHD4 introduces an intermolecular disulfide bond that links MICU1 and MICU2 into a heterodimer in the mitochondrial intermembrane space. This MICU1-MICU2 heterodimer binds MCU at low Ca2+ concentrations and dissociates upon high Ca2+ to release channel inhibition; absence of the disulfide bond increases receptor-induced mitochondrial Ca2+ uptake. |
Mia40 interactome analysis, disulfide bond biochemistry, co-immunoprecipitation, mitochondrial Ca2+ uptake assays with Ca2+ titration |
Cell metabolism |
High |
26387864
|
| 2017 |
MICU2 regulates the threshold and gain of MICU1-mediated inhibition and activation of MCU. MICU1 alone can mediate gatekeeping and cooperative activation; MICU2's fundamental role is to modulate these MICU1 functions, spatially restricting Ca2+ crosstalk between InsP3R and MCU channels. |
Patch-clamp electrophysiology of MCU channel activity over quantitatively controlled cytoplasmic Ca2+ concentrations in cells with defined MICU1/MICU2 expression |
Cell reports |
High |
29241542
|
| 2019 |
X-ray crystal structure of apo MICU2 at 2.5 Å reveals two-lobe architecture with canonical (EF1, EF4) and structural (EF2, EF3) EF-hands; MICU2 forms a symmetrical homodimer via hydrophobic contacts between EF1 and EF3 of opposing monomers—the same interface used in MICU1 dimers allowing homo/heterodimer exchange. MICU2's C-terminal helix is dispensable in vitro for MICU1 interaction but required for MICU2 function in cells. |
X-ray crystallography (2.5 Å), mutagenesis, in vitro binding assays, cellular functional assays |
Proceedings of the National Academy of Sciences of the United States of America |
High |
30755530
|
| 2020 |
Cryo-EM structure of the MCU-EMRE-MICU1-MICU2 holocomplex at 3.3 Å shows that a uniporter interaction domain on MICU1 binds a channel receptor site formed by MCU and EMRE subunits to inhibit ion flow under resting Ca2+ conditions, analogous to toxin block of neuronal channels. A Ca2+-bound MICU1-MICU2 structure at 3.1 Å reveals the Ca2+-dependent conformational changes that relieve this inhibition. |
Cryo-EM structure determination (3.3 Å and 3.1 Å), structural analysis of Ca2+-free and Ca2+-bound states |
eLife |
High |
32667285
|
| 2016 |
MICU2 exists as a monomer in Ca2+-free conditions and forms a dimer in Ca2+-bound conditions; mutation of the first EF-hand abolishes Ca2+-induced dimerization. In addition to disulfide bonds, salt bridges contribute to MICU1-MICU2 heterodimer formation. |
Size exclusion chromatography, multi-angle laser light scattering, EF-hand mutagenesis, pull-down assay, co-immunoprecipitation |
Biology open |
Medium |
27334695
|
| 2017 |
MICU2 deficiency in cardiomyocytes causes delayed sarcomere relaxation and cytosolic calcium reuptake kinetics (diastolic dysfunction), and Micu2-knockout mice show cardiovascular pathology including left atrial enlargement and vulnerability to angiotensin II-induced aortic rupture, establishing a functional role for MICU2 in cardiac calcium homeostasis. |
Micu2 knockout mice, cardiomyocyte calcium imaging, sarcomere relaxation measurements, angiotensin II infusion challenge, RNA-seq |
Proceedings of the National Academy of Sciences of the United States of America |
Medium |
29073106
|
| 2021 |
MICU2 is required for mitochondrial Ca2+ uptake in pancreatic β cells; MICU2 silencing abrogates glucose-stimulated insulin secretion (GSIS), prevents mitochondrial membrane hyperpolarization, lowers ATP/ADP ratio in response to glucose, and causes Ca2+ accumulation in the submembrane compartment that desensitizes voltage-dependent Ca2+ channels. |
siRNA silencing in INS-1 832/13 and EndoC-βH1 cells, Micu2-/- mice, live confocal imaging of mitochondrial Ca2+ and membrane potential, submembrane Ca2+ measurement, insulin secretion assays |
Molecular metabolism |
High |
33932586
|
| 2025 |
MICU2 is present in the developing mouse brain but disappears upon maturation. MICU2 loss augments mitochondrial matrix Ca2+ rise in primary cortical neurons without affecting cytoplasmic Ca2+, leading to neuronal overmigration in the cortex. MICU2-deficient patient fibroblasts replicate the mitochondria-confined Ca2+ alteration seen in developing neurons. |
MICU2 knockout mice, primary cortical neuron Ca2+ imaging, cortical migration analysis (in vivo), patient fibroblast functional assays |
Cell reports |
Medium |
41273721
|
| 2024 |
MICU1 and MICU2 gate MCU in the mammalian heart; MICU1 is present in a complex with MCU in nonfailing human hearts, and MICU1 deletion in mice alters cardiomyocyte mitochondrial Ca2+ signaling and energy metabolism with compensatory upregulation of EMRE and subsequently MCU turnover. |
Co-immunoprecipitation from human heart tissue, MICU1 knockout mice, mitochondrial Ca2+ influx measurements, pharmacology |
Proceedings of the National Academy of Sciences of the United States of America |
Medium |
39163336
|