MCU

Summary

MCU (mitochondrial calcium uniporter, HGNC:23526) is a protein-coding gene on chromosome 10q22.1, encoding Calcium uniporter protein, mitochondrial (Q8NE86). Channel-forming and calcium-conducting subunit of the mitochondrial inner membrane calcium uniporter complex (uniplex), which mediates calcium uptake into the mitochondrial matrix.

Enables calcium channel activity; identical protein binding activity; and uniporter activity. Involved in several processes, including cellular response to calcium ion starvation; positive regulation of mitochondrial calcium ion concentration; and positive regulation of mitochondrial fission. Located in mitochondrion. Part of uniplex complex. Is active in mitochondrial inner membrane.

Source: NCBI Gene 90550 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 32 total
• Druggable target: yes
• MANE Select transcript: NM_138357

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23526
Approved symbol	MCU
Name	mitochondrial calcium uniporter
Location	10q22.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ46135
Ensembl gene	ENSG00000156026
Ensembl biotype	protein_coding
OMIM	614197
Entrez	90550

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 6 protein_coding, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000357157, ENST00000373053, ENST00000483185, ENST00000536019, ENST00000603118, ENST00000603649, ENST00000604152, ENST00000604372, ENST00000604679, ENST00000605416, ENST00000605597, ENST00000857903, ENST00000857904

RefSeq mRNA: 3 — MANE Select: NM_138357 NM_001270679, NM_001270680, NM_138357

CCDS: CCDS59218, CCDS59219, CCDS7317

Canonical transcript exons

ENST00000373053 — 8 exons

Exon	Start	End
ENSE00001459415	72885745	72887694
ENSE00001855279	72692143	72692301
ENSE00003514140	72860423	72860527
ENSE00003516544	72871377	72871580
ENSE00003607744	72834359	72834428
ENSE00003621326	72868703	72868863
ENSE00003640269	72859177	72859347
ENSE00003651652	72884266	72884382

Expression profiles

Bgee: expression breadth ubiquitous, 226 present calls, max score 96.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.2405 / max 2409.7192, expressed in 1823 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
105510	30.2350	1823
105509	1.0055	658

Top tissues by expression

247 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tibialis anterior	UBERON:0001385	96.47	gold quality
ileal mucosa	UBERON:0000331	95.63	gold quality
rectum	UBERON:0001052	94.29	gold quality
deltoid	UBERON:0001476	94.03	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.84	gold quality
muscle of leg	UBERON:0001383	93.73	gold quality
gastrocnemius	UBERON:0001388	93.63	gold quality
cerebellar hemisphere	UBERON:0002245	93.36	gold quality
cerebellar cortex	UBERON:0002129	93.33	gold quality
mucosa of transverse colon	UBERON:0004991	92.68	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.63	gold quality
cerebellum	UBERON:0002037	92.43	gold quality
lower esophagus mucosa	UBERON:0035834	91.81	gold quality
skeletal muscle tissue	UBERON:0001134	91.46	gold quality
colonic epithelium	UBERON:0000397	90.96	gold quality
gall bladder	UBERON:0002110	90.83	gold quality
biceps brachii	UBERON:0001507	90.53	gold quality
calcaneal tendon	UBERON:0003701	90.47	gold quality
transverse colon	UBERON:0001157	90.39	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	89.96	gold quality
muscle tissue	UBERON:0002385	89.94	gold quality
quadriceps femoris	UBERON:0001377	89.92	gold quality
bone marrow cell	CL:0002092	89.79	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.28	gold quality
smooth muscle tissue	UBERON:0001135	89.12	gold quality
colonic mucosa	UBERON:0000317	89.10	gold quality
vastus lateralis	UBERON:0001379	88.98	gold quality
cortical plate	UBERON:0005343	88.70	gold quality
nasal cavity epithelium	UBERON:0005384	88.67	gold quality
duodenum	UBERON:0002114	88.62	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.13
E-MTAB-9801	yes	6.69

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NPAS4

miRNA regulators (miRDB)

115 targeting MCU, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3646	100.00	73.56	5283
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-3148	99.97	75.06	6478

Literature-anchored findings (GeneRIF, showing 40)

• CCDC109A was identified in this large-scale proteomics analysis as a mitochondrial protein broadly expressed in many mouse tissues. The human protein was also confirmed to localize to mitochondria. (PMID:18614015)
• MCU is an oligomeric protein residing in the mitochondrial inner membrane that interacts with MICU1 and is necessary for mitochondrial calcium uniport. (PMID:21685886)
• Functional characterization of the MCU protein; shows that it is necessary for mitochondrial calcium uptake. (PMID:21685888)
• the crucial role of MICU1 and MCU in mitochondrial Ca(2+) uptake in pancreatic beta-cells and their involvement in the positive feedback required for sustained insulin secretion. (PMID:22904319)
• The mitochondrial calcium uniporter (MCU): molecular identity and physiological roles. (PMID:23400777)
• study demonstrates that MCU overexpression is a feature of some breast cancers and that MCU overexpression may offer a survival advantage against some cell death pathways (PMID:23602897)
• analyses establish that MCU encodes the pore-forming subunit of the uniporter channel (PMID:23755363)
• We review not only the biochemical identities and structures of the proteins required for mitochondrial Ca2+ uptake but also their implications in different physiopathological contexts. [review] (PMID:24366263)
• SLC25A23 augments mitochondrial Ca(2) uptake, interacts with MCU, and induces oxidative stress-mediated cell death. (PMID:24430870)
• ERp57 can regulate the expression of the mitochondrial calcium uniporter (MCU) and modulate mitochondrial calcium uptake (PMID:24815697)
• MCU plays a critical role in breast cancer cell migration by regulating store-operated Ca(2) entry. (PMID:25640838)
• MCU-VDAC1 complex regulates mitochondrial Ca(2+) uptake and oxidative stress-induced apoptosis (PMID:25753332)
• Loss of heterozygosity of MCU gene on chromosome 10q is associated with pancreatic cancer. (PMID:25824785)
• Studies indicate the existence of an inner mitochondrial protein termed the mitochondrial calcium uniporter for calcium transport. (PMID:25999421)
• results suggest that N terminal domain of MCU is essential for the modulation of MCU function, although it does not affect the uniplex formation (PMID:26341627)
• Our experiments provide novel details about how MCU/EMRE is regulated by MICU1 and an original approach to investigate MCU/EMRE activation in intact cells. (PMID:26489515)
• The molecular structure and regulation of the MCU complex in addition to its pathophysiological role are discussed with particular attention to striated muscle tissues. Review. (PMID:26968367)
• Data suggest that MCU regulator (EMRE) might be a structural factor for opening of the mitochondrial calcium uniporter (MCU)-forming pore. (PMID:27001609)
• Here, the authors 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. (PMID:27099988)
• MCU downregulation hampered cell motility and invasiveness and reduced tumor growth, lymph node infiltration, and lung metastasis in triple-negative breast cancer xenografts. In MCU-silenced cells, production of mitochondrial reactive oxygen species (mROS) is blunted and expression of the hypoxia-inducible factor-1alpha (HIF-1alpha) is reduced, suggesting a signaling role for mROS and HIF-1alpha, downstream of mitochon… (PMID:27138568)
• Study indicates that inhibition of mitochondrial calcium uniporter can inhibit excessive mitophagy and protect the neurocytes from ischemia/reperfusion injury. (PMID:27288019)
• decreased MCU expression in hypertensive with mutation cells contributed to dysregulated Ca(2+) uptake into the mitochondria (PMID:27471128)
• It has been shown that the propagation of the TRPV1-induced cytosolic calcium and sodium fluxes into mitochondria is dependent on coordinated activity of NCLX and MCU. (PMID:27627464)
• Mitochondrial Ca(2+) uptake is controlled by protein arginine methyl transferase 1 that asymmetrically methylates MICU1, resulting in decreased Ca(2+) sensitivity. UCP2/3 normalize Ca(2+) sensitivity of methylated MICU1 and, thus, re-establish mitochondrial Ca(2+) uptake activity. (PMID:27642082)
• The studies findings in aging human skeletal muscle confirm the data obtained in mice and propose mitochondrial calcium uniporter and mitochondria-related proteins as potential pharmacological targets to counteract age-related muscle loss. (PMID:28039397)
• Reveal a distinct functional role for Cys-97 in mitochondrial reactive oxygen species sensing and regulation of MCU activity. (PMID:28262504)
• Regulation of mitochondrial Ca(2+) suggests that MCU may play a pivotal role in the development of fibrosis and could potentially be a therapeutic target for pulmonary fibrosis. (PMID:28351840)
• The results highlight the dynamic nature of uniporter subunit assembly, which must be tightly regulated to ensure proper mitochondrial responses to intracellular Ca(2+) signals. (PMID:28396416)
• High MCU expression is associated with metastasis in hepatocellular carcinoma. (PMID:28650465)
• Mitochondrial calcium uniporter plays an important role in hyperglycaemia-induced endothelial cell dysfunction. (PMID:28777009)
• MCU expression returned to physiological levels in visceral adipose tissue of patients after weight loss by bariatric surgery. Altered mitochondrial calcium flux in fat cells may play a role in obesity and diabetes and may be associated with the differential metabolic profiles of visceral and subcutaneous adipose tissue. (PMID:28790027)
• MICU2 restricts spatial crosstalk between InsP3R and MCU channels by regulating threshold and gain of MICU1-mediated inhibition and activation of MCU. (PMID:29241542)
• VDAC1 allows Ca(2+) access to the MCU, facilitating transport of Ca(2+) to the matrix, and also from the IMS to the cytosol. Intra-mitochondrial Ca(2+) controls energy production and metabolism by modulating critical enzymes in the tricarboxylic acid (TCA) cycle and fatty acid oxidation. (PMID:29594867)
• Wild-type TRPM2 but not Ca(2+)-impermeable mutant E960D reconstituted phosphorylation and expression of Pyk2 and CREB in TRPM2-depleted cells exposed to doxorubicin. Results demonstrate that TRPM2 expression protects the viability of neuroblastoma through Src, Pyk2, CREB, and MCU activation, which play key roles in maintaining mitochondrial function and cellular bioenergetics (PMID:30020827)
• MICU1 imparts the mitochondrial uniporter with the ability to discriminate between Ca(2+) and Mn(2+). (PMID:30082385)
• MICU1 deletion sensitizes human cells to manganese-dependent cell death by disinhibiting MCU-mediated manganese uptake. (PMID:30403999)
• MICU1 confers Ca(2+)-dependent gating of the uniporter by blocking/unblocking MCU. (PMID:30638448)
• These observations suggest that macrophage MCU-mediated metabolic reprogramming contributes to fibrotic repair after lung injury. (PMID:31473487)
• MCU deficiency blocks cell proliferation by disrupting cytoplasmic Ca2+ transients due to altered Drp1 hospitalization. (PMID:31907514)
• Mitochondrial pyruvate and fatty acid flux modulate MICU1-dependent control of MCU activity. (PMID:32317369)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mcu	ENSDARG00000101175
mus_musculus	Mcu	ENSMUSG00000009647
rattus_norvegicus	Mcu	ENSRNOG00000045920
drosophila_melanogaster	MCU	FBGN0042185
caenorhabditis_elegans		WBGENE00019296

Paralogs (1): MCUB (ENSG00000005059)

Protein

Protein identifiers

Calcium uniporter protein, mitochondrial — Q8NE86 (reviewed: Q8NE86)

Alternative names: Coiled-coil domain-containing protein 109A

All UniProt accessions (6): Q8NE86, S4R319, S4R332, S4R3F5, S4R3W8, S4R468

UniProt curated annotations — full annotation on UniProt →

Function. Channel-forming and calcium-conducting subunit of the mitochondrial inner membrane calcium uniporter complex (uniplex), which mediates calcium uptake into the mitochondrial matrix. MCU channel activity is regulated by the calcium-sensor subunits of the uniplex MICU1 and MICU2 (or MICU3). Mitochondrial calcium homeostasis plays key roles in cellular physiology and regulates ATP production, cytoplasmic calcium signals and activation of cell death pathways. Involved in buffering the amplitude of systolic calcium rises in cardiomyocytes. While dispensable for baseline homeostatic cardiac function, acts as a key regulator of short-term mitochondrial calcium loading underlying a ‘fight-or-flight’ response during acute stress: acts by mediating a rapid increase of mitochondrial calcium in pacemaker cells. Participates in mitochondrial permeability transition during ischemia-reperfusion injury. Mitochondrial calcium uptake in skeletal muscle cells is involved in muscle size in adults. Regulates synaptic vesicle endocytosis kinetics in central nerve terminal. Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake. Involved in antigen processing and presentation.

Subunit / interactions. Homotetramer. Component of the uniplex complex, composed of MCU, EMRE/SMDT1, MICU1 and MICU2 (or MICU3) in a 4:4:1:1 stoichiometry. Interacts with CCDC109B/MCUB; this inhibits channel activity. Interacts with MCUR1. Interactions with MICU1 and MCUR1 are mutually exclusive. Interacts with SLC25A23.

Subcellular location. Mitochondrion inner membrane.

Post-translational modifications. Phosphorylation by CaMK2 in heart leads to increased MCU current. The regulation of MCU by CaMK2 is however subject to discussion: another group was unable to reproduce these results. Phosphorylated on tyrosines by PTK2B/PYK2, promoting oligomerization. Glutathionylation at Cys-97 in response to reactive oxygen species (ROS) promotes MCU higher-order assembly, leading to constitutive activation of the MCU channel and mitochondrial calcium overload. Undergoes proteolytic degradation by SPG7.

Activity regulation. MCU channel activity is regulated by the heterodimer composed of MICU1 and either MICU2 or MICU3, which act as calcium-sensors. At low calcium levels, MICU1 occludes the pore of the MCU channel, preventing mitochondrial calcium uptake. At higher calcium levels, calcium-binding to MICU1 and MICU2 (or MICU3) induces a conformational change that weakens MCU-MICU1 interactions and moves the MICU1-MICU2 heterodimer away from the pore, allowing calcium permeation through the channel. MCU channel activity is gated by EMRE/SMDT1 via the juxtamembrane helix loop. Inhibited by ruthenium red or its derivative Ru360.

Domain organisation. The selectivity filter, in which calcium ions are arranged in single file, is composed of two acidic rings separated by one helical turn along the central axis of the channel pore. The N-terminal MCU domain is required for efficient Ca(2+) uptake and for interaction with MCUR1. It is not required for targeting to the mitochondria, oligomerization, interaction with MICU1 and MICU2, or assembly of the uniplex complex.

Induction. MCU transcripts are down-regulated by microRNA miR-25. Down-regulation by miR-25 may protect cardiomyocytes against oxidative damage in cardiomyocytes.

Similarity. Belongs to the MCU (TC 1.A.77) family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8NE86-1	1	yes
Q8NE86-2	2
Q8NE86-3	3

RefSeq proteins (3): NP_001257608, NP_001257609, NP_612366* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006769	MCU_C	Domain
IPR039055	MCU_fam	Family

Pfam: PF04678

Catalyzed reactions (Rhea), 1 shown:

• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)

UniProt features (88 total): mutagenesis site 37, helix 16, strand 11, modified residue 4, topological domain 3, turn 3, coiled-coil region 2, splice variant 2, transmembrane region 2, sequence conflict 2, region of interest 2, transit peptide 1, chain 1, short sequence motif 1, binding site 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
4XTB	X-RAY DIFFRACTION	1.5
5KUE	X-RAY DIFFRACTION	1.5
5KUJ	X-RAY DIFFRACTION	1.6
8URG	X-RAY DIFFRACTION	1.63
4XSJ	X-RAY DIFFRACTION	1.8
5KUG	X-RAY DIFFRACTION	1.9
6JG0	X-RAY DIFFRACTION	2.5
5KUI	X-RAY DIFFRACTION	2.7
5BZ6	X-RAY DIFFRACTION	2.75
6KVX	X-RAY DIFFRACTION	2.85
6WDN	ELECTRON MICROSCOPY	3.2
6K7X	ELECTRON MICROSCOPY	3.27
6K7Y	ELECTRON MICROSCOPY	3.6
6O5B	ELECTRON MICROSCOPY	3.6
6WDO	ELECTRON MICROSCOPY	3.6
6O58	ELECTRON MICROSCOPY	3.8
6XJV	ELECTRON MICROSCOPY	4.17
6XJX	ELECTRON MICROSCOPY	4.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NE86-F1	80.30	0.60

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (1): 264

Post-translational modifications (4): 57, 92, 97, 332

Mutagenesis-validated functional residues (37):

Position	Phenotype
57	decreased mcu current; when associated with a-92.
66	does not affect glutathionylation in response to reactive oxygen species.
92	decreased mcu current; when associated with a-57.
92	impairs calcium uptake, but has no effect on oligomerization and interaction with micu1 and micu2.
97	abolished glutathionylation in response to reactive oxygen species.
123	no effect on calcium uptake in presence of high concentrations of calcium. abolished dimerization of mcu.
180	no effect on calcium uptake, oligomerization and interaction with micu1 and micu2.
191	does not affect glutathionylation in response to reactive oxygen species.
240	abolished calcium uptake.
241	abolished interaction with emre/smdt1 and calcium uptake.
248	abolished calcium uptake.
257	according to a report, inhibits calcium uptake. according to a subsequent report, does not affect greatly calcium uptake
257	does not affect greatly calcium uptake.
259	does not inhibit calcium uptake. strongly reduced sensitivity to ruthenium red inhibition.
259	prevents entrance of calcium into the pore.
260	abolished mitochondrial calcium uptake.
261–264	dominant negative (dn) mutant; inhibits calcium uptake. inhibits calcium channel activity. expression of the dominant ne
261	abolished interaction with micu1.
261	partially functional; does not completely abolish calcium channel activity. does not affect interaction with micu1.
262	does not affect mitochondrial calcium uptake.
263	reduced but not abolished mitochondrial calcium uptake.
264	does not affect interaction with micu1.
264	abolished mitochondrial calcium uptake.
265	abolished mitochondrial calcium uptake.
267	reduced mitochondrial calcium uptake.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8949215	Mitochondrial calcium ion transport
R-HSA-8949664	Processing of SMDT1
R-HSA-382551	Transport of small molecules

MSigDB gene sets: 273 (showing top): AAGCAAT_MIR137, GOBP_POSITIVE_REGULATION_OF_MITOCHONDRIAL_FISSION, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_INSULIN_SECRETION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, CACCAGC_MIR138, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_REGULATION_OF_LEUKOCYTE_MIGRATION, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_LEUKOCYTE_CHEMOTAXIS

GO Biological Process (18): generation of precursor metabolites and energy (GO:0006091), mitochondrial calcium ion transmembrane transport (GO:0006851), cell population proliferation (GO:0008283), cell migration (GO:0016477), calcium-mediated signaling (GO:0019722), positive regulation of insulin secretion (GO:0032024), calcium import into the mitochondrion (GO:0036444), glucose homeostasis (GO:0042593), protein complex oligomerization (GO:0051259), mitochondrial calcium ion homeostasis (GO:0051560), positive regulation of mitochondrial calcium ion concentration (GO:0051561), cellular response to calcium ion starvation (GO:0072732), positive regulation of neutrophil chemotaxis (GO:0090023), positive regulation of mitochondrial fission (GO:0090141), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (4): calcium channel activity (GO:0005262), uniporter activity (GO:0015292), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), calcium channel complex (GO:0034704), uniplex complex (GO:1990246), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Transport of small molecules	1
Mitochondrial calcium ion transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metabolic process	1
calcium ion transmembrane transport	1
cellular process	1
cell motility	1
intracellular signaling cassette	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
mitochondrial calcium ion transmembrane transport	1
intercellular transport	1
carbohydrate homeostasis	1
protein-containing complex assembly	1
mitochondrion	1
intracellular calcium ion homeostasis	1
mitochondrial calcium ion homeostasis	1
cellular response to starvation	1
neutrophil chemotaxis	1
positive regulation of granulocyte chemotaxis	1
regulation of neutrophil chemotaxis	1
positive regulation of neutrophil migration	1
mitochondrial fission	1
positive regulation of organelle organization	1
positive regulation of developmental process	1
regulation of mitochondrial fission	1
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
secondary active transmembrane transporter activity	1
protein binding	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1

Protein interactions and networks

STRING

1142 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCU	MICU1	Q9BPX6	996
MCU	MICU2	Q8IYU8	995
MCU	SMDT1	Q9H4I9	988
MCU	VDAC1	P21796	933
MCU	MCUR1	Q96AQ8	910
MCU	MICU3	Q86XE3	900
MCU	ITPR3	Q14573	883
MCU	ITPR1	Q14643	882
MCU	HSPA9	P30036	845
MCU	SLC8B1	Q6J4K2	789
MCU	MFN2	O95140	762
MCU	LETM1	O95202	752
MCU	SLC25A23	Q9BV35	742
MCU	MFN1	Q8IWA4	717
MCU	RHOT1	Q8IXI2	683

IntAct

127 interactions, top by confidence:

A	B	Type	Score
RAD51D	RAD51B	psi-mi:“MI:0914”(association)	0.850
MICU1	MICU2	psi-mi:“MI:0914”(association)	0.780
MCU	SMDT1	psi-mi:“MI:0915”(physical association)	0.760
MCU	MICU1	psi-mi:“MI:0915”(physical association)	0.740
MCU	MICU1	psi-mi:“MI:0403”(colocalization)	0.740
MICU1	MCU	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ASPH	STXBP3	psi-mi:“MI:0914”(association)	0.640
RAC1	COX6C	psi-mi:“MI:0914”(association)	0.640
NDUFA9	NDUFS8	psi-mi:“MI:0914”(association)	0.530
TOR1AIP2	TMEM223	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
SLC15A1	METTL15	psi-mi:“MI:0914”(association)	0.530
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
MCU	MICU2	psi-mi:“MI:0914”(association)	0.530
PDCD1	RTL8C	psi-mi:“MI:0914”(association)	0.530
ARMC6	SLC27A2	psi-mi:“MI:0914”(association)	0.530
IRGC	RAP1GDS1	psi-mi:“MI:0914”(association)	0.530
SMDT1	MICU2	psi-mi:“MI:0915”(physical association)	0.490

BioGRID (242): MCU (Affinity Capture-MS), MCU (Affinity Capture-MS), MCU (Affinity Capture-MS), MCU (Affinity Capture-MS), MCU (Affinity Capture-MS), MCU (Affinity Capture-MS), MCU (Affinity Capture-MS), MCU (Affinity Capture-MS), MCU (Affinity Capture-MS), MCU (Affinity Capture-MS), MCU (Affinity Capture-MS), MCU (Affinity Capture-MS), MCU (Affinity Capture-MS), MCU (Affinity Capture-MS), MCU (Affinity Capture-MS)

ESM2 similar proteins: A0A7C9FSB8, A2TLM1, A6H7H7, B8BKI7, B9N1F9, B9SQI7, D2XV59, E0CSI1, F1N9S8, O00178, O08582, O35586, O35760, O48964, O48965, O76031, O81770, P11029, P11497, P58044, P69341, Q0J035, Q13085, Q13907, Q14165, Q1LZ95, Q1LZ96, Q28559, Q2R483, Q38929, Q39471, Q39472, Q39664, Q3UMR5, Q42553, Q4R4W5, Q5NVE1, Q5R8R6, Q5SWU9, Q5U2U0

Diamond homologs: D6WIX5, F4I111, O64823, Q08BI9, Q21121, Q3UMR5, Q54LT0, Q810S1, Q8IQ70, Q8NE86, Q8VYR0, Q9FJV7, Q9LVR5, Q9NWR8, A0A0E0RX65, Q1PE15, Q7S4I4, W2SDE2, A1CWT6, E9DVV4

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
MCU	“form complex”	MCU_MICUB_variant	binding
MCU	“form complex”	MCU_MICU1_variant	binding
MCU	“form complex”	MCU_MICU3_variant	binding
MCU	“form complex”	MCU_MICU2_variant	binding
PRKAA1	“up-regulates activity”	MCU	phosphorylation
AMPK	“up-regulates activity”	MCU	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 147 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SLC-mediated transmembrane transport	10	5.6×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

32 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	21
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3176 predictions. Top by Δscore:

Variant	Effect	Δscore
10:72715106:TTTA:T	acceptor_loss	1.0000
10:72715109:A:AG	acceptor_gain	1.0000
10:72715109:A:G	acceptor_loss	1.0000
10:72715110:G:GG	acceptor_gain	1.0000
10:72715222:GTCAA:G	donor_gain	1.0000
10:72715225:AAG:A	donor_loss	1.0000
10:72715226:AG:A	donor_loss	1.0000
10:72715227:G:GG	donor_gain	1.0000
10:72715228:TAAG:T	donor_loss	1.0000
10:72809135:T:TA	donor_gain	1.0000
10:72809136:AGT:A	donor_gain	1.0000
10:72809139:AGT:A	donor_gain	1.0000
10:72834355:CTA:C	acceptor_loss	1.0000
10:72834356:TA:T	acceptor_loss	1.0000
10:72834357:A:AG	acceptor_gain	1.0000
10:72834358:G:GA	acceptor_gain	1.0000
10:72834358:GGT:G	acceptor_gain	1.0000
10:72834425:GATG:G	donor_gain	1.0000
10:72834426:ATGGT:A	donor_loss	1.0000
10:72834427:TGGT:T	donor_loss	1.0000
10:72834428:GGTG:G	donor_loss	1.0000
10:72834429:G:GG	donor_gain	1.0000
10:72834430:T:A	donor_loss	1.0000
10:72859175:A:AG	acceptor_gain	1.0000
10:72859176:G:GG	acceptor_gain	1.0000
10:72859176:GAT:G	acceptor_gain	1.0000
10:72859343:ACCAG:A	donor_loss	1.0000
10:72859344:CCAG:C	donor_loss	1.0000
10:72859345:CAG:C	donor_loss	1.0000
10:72859346:AG:A	donor_loss	1.0000

AlphaMissense

2256 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:72859252:T:C	F99S	1.000
10:72871441:C:A	A241D	1.000
10:72871449:G:C	A244P	1.000
10:72871450:C:A	A244D	1.000
10:72871458:T:C	F247L	1.000
10:72871460:T:A	F247L	1.000
10:72871460:T:G	F247L	1.000
10:72871462:G:A	G248D	1.000
10:72871471:C:A	A251D	1.000
10:72871477:T:C	L253P	1.000
10:72871482:T:A	W255R	1.000
10:72871482:T:C	W255R	1.000
10:72871484:G:C	W255C	1.000
10:72871484:G:T	W255C	1.000
10:72871491:T:C	Y258H	1.000
10:72871495:C:T	S259F	1.000
10:72871497:T:A	W260R	1.000
10:72871497:T:C	W260R	1.000
10:72871498:G:C	W260S	1.000
10:72871499:G:C	W260C	1.000
10:72871499:G:T	W260C	1.000
10:72871500:G:C	D261H	1.000
10:72871501:A:C	D261A	1.000
10:72871501:A:G	D261G	1.000
10:72871501:A:T	D261V	1.000
10:72871507:T:A	M263K	1.000
10:72871507:T:G	M263R	1.000
10:72871511:G:C	E264D	1.000
10:72871511:G:T	E264D	1.000
10:72871512:C:T	P265S	1.000

dbSNP variants (sampled 300 via entrez): RS1000002936 (10:72825026 G>A), RS1000031837 (10:72823054 C>T), RS1000047285 (10:72734011 T>C), RS1000082840 (10:72779052 C>G), RS1000083818 (10:72885888 A>G,T), RS1000084995 (10:72811269 T>C), RS1000101563 (10:72741058 G>A), RS1000113296 (10:72832076 G>GT), RS1000146016 (10:72823306 A>T), RS1000167262 (10:72694442 C>T), RS1000171348 (10:72869945 C>A), RS1000177198 (10:72715298 A>G), RS1000191728 (10:72806788 C>T), RS1000195625 (10:72853693 GA>G), RS1000198131 (10:72694231 A>G)

Disease associations

OMIM: gene MIM:614197 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST009152_5	Triglyceride levels	7.000000e-20
GCST010002_290	Refractive error	2.000000e-17
GCST90002404_492	Red cell distribution width	2.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067356 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.48	Kd	333.2	nM	CHEMBL5653589
6.45	ED50	356.3	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148736: Binding affinity to human MCU incubated for 45 mins by Kinobead based pull down assay	kd	0.3332	uM

CTD chemical–gene interactions

47 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	decreases expression, increases abundance, affects methylation	2
Cyclosporine	increases expression, decreases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
GSK-J4	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	decreases methylation	1
sodium arsenate	decreases expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression, increases abundance	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	increases abundance, increases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
cylindrospermopsin	increases expression	1
Ru 360	decreases reaction, increases cleavage, increases expression, affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
2-(1-hydroxy-4-oxocyclohexa-2,5-dienyl)pyran-4-one	decreases reaction, increases reaction, increases expression, affects reaction, decreases expression (+2 more)	1
bisphenol AF	increases expression	1
Acetaminophen	increases expression	1
Acrolein	increases oxidation, increases abundance, affects cotreatment	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression, increases abundance	1
Homocysteine	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651778	Binding	Binding affinity to human MCU incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E0HS	Ubigene HeLa MCU KO	Cancer cell line	Female
CVCL_E1D2	Ubigene THP-1 MCU KO	Cancer cell line	Male
CVCL_E1KS	HyCyte HeLa KO-hMCU	Cancer cell line	Female
CVCL_KT74	HeLa SilenciX MCU	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.