MCUB

Summary

MCUB (mitochondrial calcium uniporter dominant negative subunit beta, HGNC:26076) is a protein-coding gene on chromosome 4q25, encoding Calcium uniporter regulatory subunit MCUb, mitochondrial (Q9NWR8). Negative regulator of the mitochondrial calcium uniporter (MCU), a channel that mediates calcium uptake into the mitochondrial matrix.

Enables calcium channel inhibitor activity. Involved in negative regulation of calcium import into the mitochondrion. Located in cytosol and mitochondrial inner membrane. Part of uniplex complex.

Source: NCBI Gene 55013 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 8 total
• MANE Select transcript: NM_017918

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26076
Approved symbol	MCUB
Name	mitochondrial calcium uniporter dominant negative subunit beta
Location	4q25
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20647
Ensembl gene	ENSG00000005059
Ensembl biotype	protein_coding
OMIM	620702
Entrez	55013

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 2 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000394650, ENST00000452915, ENST00000472310, ENST00000494604, ENST00000515114, ENST00000867447

RefSeq mRNA: 1 — MANE Select: NM_017918 NM_017918

CCDS: CCDS3683

Canonical transcript exons

ENST00000394650 — 8 exons

Exon	Start	End
ENSE00000333811	109685251	109685367
ENSE00000736521	109682582	109682742
ENSE00000736563	109684443	109684646
ENSE00001866116	109687515	109688719
ENSE00002034107	109560246	109560436
ENSE00003495138	109659011	109659086
ENSE00003523118	109664290	109664394
ENSE00003572414	109660195	109660365

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 97.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.2770 / max 432.1676, expressed in 1770 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49236	27.3623	1756
49235	3.1179	1323
49239	1.6827	919
49237	1.2375	697
49234	0.5408	299
49238	0.3357	133

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	97.05	gold quality
mononuclear cell	CL:0000842	97.04	gold quality
leukocyte	CL:0000738	96.83	gold quality
germinal epithelium of ovary	UBERON:0001304	94.31	gold quality
secondary oocyte	CL:0000655	94.02	gold quality
palpebral conjunctiva	UBERON:0001812	93.13	gold quality
granulocyte	CL:0000094	92.86	gold quality
lymph node	UBERON:0000029	91.97	gold quality
vermiform appendix	UBERON:0001154	90.76	gold quality
gingival epithelium	UBERON:0001949	90.62	gold quality
blood	UBERON:0000178	90.07	gold quality
oocyte	CL:0000023	89.78	gold quality
calcaneal tendon	UBERON:0003701	89.61	gold quality
cervix squamous epithelium	UBERON:0006922	89.57	gold quality
parietal pleura	UBERON:0002400	89.47	gold quality
gingiva	UBERON:0001828	89.01	gold quality
thymus	UBERON:0002370	88.99	gold quality
epithelium of nasopharynx	UBERON:0001951	88.46	gold quality
squamous epithelium	UBERON:0006914	88.26	gold quality
pleura	UBERON:0000977	88.13	gold quality
superficial temporal artery	UBERON:0001614	87.61	gold quality
caecum	UBERON:0001153	87.34	gold quality
esophagus squamous epithelium	UBERON:0006920	87.22	gold quality
ventricular zone	UBERON:0003053	87.08	gold quality
bone marrow	UBERON:0002371	86.80	gold quality
spleen	UBERON:0002106	86.36	gold quality
subcutaneous adipose tissue	UBERON:0002190	86.23	gold quality
visceral pleura	UBERON:0002401	86.22	gold quality
omental fat pad	UBERON:0010414	86.05	gold quality
peritoneum	UBERON:0002358	86.01	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	14.36
E-ANND-3	yes	10.77
E-MTAB-4850	no	2144.08

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

8 targeting MCUB, 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-548AW	99.99	72.57	3559
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4684-3P	98.24	69.91	1075
HSA-MIR-495-5P	97.62	68.28	682

Literature-anchored findings (GeneRIF, showing 3)

• MCUb (also known as CCDC109b) is a paralogue of MCU (CCDC109a). MCUb physically resides within the mitochondrial uniporter complex (uniplex), which consists of the MCU, MCUb, EMRE, MICU1, and MICU2. (PMID:24231807)
• This study elucidated a role for CCDC109B as an oncogene and a prognostic marker in human gliomas. (PMID:28754121)
• MCUB-dependent changes in mitochondrial calcium uniporter stoichiometry are a prominent regulatory mechanism to modulate mitochondrial Ca(2+) uptake and cardiac myocyte cellular physiology. (PMID:31533452)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Mcub	ENSMUSG00000027994
rattus_norvegicus	Mcub	ENSRNOG00000009433

Paralogs (1): MCU (ENSG00000156026)

Protein

Protein identifiers

Calcium uniporter regulatory subunit MCUb, mitochondrial — Q9NWR8 (reviewed: Q9NWR8)

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

All UniProt accessions (1): Q9NWR8

UniProt curated annotations — full annotation on UniProt →

Function. Negative regulator of the mitochondrial calcium uniporter (MCU), a channel that mediates calcium uptake into the mitochondrial matrix. MCUB is required to limit mitochondrial calcium overload during stress. Acts as a dominant-negative regulator that displaces MCU from the functional uniplex complex and thereby decreases the association of calcium sensors MICU1 and MICU2, preventing channel gating. Mitochondrial calcium homeostasis plays key roles in mitochondrial metabolism. Acts as an important regulator of mitochondrial metabolism in response to stress in muscle cells: induced in response to fasting, leading to restrict mitochondrial calcium uptake, resulting in reprogramming of mitochondria toward fatty acid oxidation preference. Acts as a regulator of macrophage polarization during skeletal muscle regeneration: inhibition of mitochondrial calcium uptake drives differentiation of macrophages with anti-inflammatory profile, promoting the differentiation and fusion of satellite cells.

Subunit / interactions. Homooligomer. Associates with the uniplex complex, composed of MCU, MICU1, MICU2 and EMRE/SMDT1, inhibiting its activity.

Subcellular location. Mitochondrion inner membrane.

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

RefSeq proteins (1): NP_060388* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006769	MCU_C	Domain
IPR039055	MCU_fam	Family

Pfam: PF04678

UniProt features (11 total): sequence variant 3, sequence conflict 2, transmembrane region 2, coiled-coil region 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NWR8-F1	75.69	0.27

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: 288 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, chr4q25, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_SKELETAL_MUSCLE_TISSUE_REGENERATION, GOBP_REGULATION_OF_SKELETAL_MUSCLE_CELL_DIFFERENTIATION, GOBP_GROWTH, GOBP_REGULATION_OF_MACROPHAGE_ACTIVATION, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_REGENERATION, HANN_RESISTANCE_TO_BCL2_INHIBITOR_UP, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_MITOCHONDRIAL_CALCIUM_ION_HOMEOSTASIS

GO Biological Process (9): mitochondrial calcium ion transmembrane transport (GO:0006851), calcium import into the mitochondrion (GO:0036444), regulation of macrophage activation (GO:0043030), skeletal muscle tissue regeneration (GO:0043403), mitochondrial calcium ion homeostasis (GO:0051560), negative regulation of calcium import into the mitochondrion (GO:0110099), positive regulation of skeletal muscle satellite cell differentiation (GO:1902726), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816)

GO Molecular Function (2): calcium channel inhibitor activity (GO:0019855), protein binding (GO:0005515)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), cytosol (GO:0005829), membrane (GO:0016020), calcium channel complex (GO:0034704), uniplex complex (GO:1990246)

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
cytoplasm	2
cellular anatomical structure	2
calcium ion transmembrane transport	1
mitochondrial calcium ion transmembrane transport	1
intercellular transport	1
regulation of leukocyte activation	1
macrophage activation	1
tissue regeneration	1
mitochondrion	1
intracellular calcium ion homeostasis	1
calcium import into the mitochondrion	1
regulation of calcium import into the mitochondrion	1
negative regulation of calcium ion transmembrane transport	1
skeletal muscle satellite cell differentiation	1
positive regulation of skeletal muscle cell differentiation	1
transport	1
metal ion transport	1
calcium channel regulator activity	1
calcium channel activity	1
ion channel inhibitor activity	1
binding	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
cation channel complex	1
calcium channel complex	1
inner mitochondrial membrane protein complex	1

Protein interactions and networks

STRING

552 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCUB	MICU2	Q8IYU8	998
MCUB	MICU1	Q9BPX6	998
MCUB	SMDT1	Q9H4I9	997
MCUB	MCUR1	Q96AQ8	997
MCUB	MICU3	Q86XE3	989
MCUB	SLC25A23	Q9BV35	833
MCUB	MCU	Q8NE86	661
MCUB	LETM1	O95202	657
MCUB	SLC8B1	Q6J4K2	649
MCUB	SLC25A3	Q00325	510
MCUB	VDAC2	P45880	502
MCUB	ITPR3	Q14573	484
MCUB	VDAC1	P21796	464
MCUB	ITPR1	Q14643	463
MCUB	CCDC3	Q9BQI4	427

IntAct

34 interactions, top by confidence:

A	B	Type	Score
FAF2	UBB	psi-mi:“MI:0914”(association)	0.640
ASPH	STXBP3	psi-mi:“MI:0914”(association)	0.640
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
SETDB1	CCDC85C	psi-mi:“MI:0914”(association)	0.530
MCUB	SETDB1	psi-mi:“MI:0915”(physical association)	0.500
SETDB1	CCDC85C	psi-mi:“MI:0914”(association)	0.350
TXNDC15	ORC4	psi-mi:“MI:0914”(association)	0.350
MRPL12		psi-mi:“MI:0914”(association)	0.350
GNAI2	GNG7	psi-mi:“MI:0914”(association)	0.350
ATAD3A	TMEM223	psi-mi:“MI:0914”(association)	0.350
	PLOD2	psi-mi:“MI:0914”(association)	0.350
SEC62	GPR89A	psi-mi:“MI:0914”(association)	0.350
TXNDC15	GET1	psi-mi:“MI:0914”(association)	0.350
SECTM1	GAPDHS	psi-mi:“MI:0914”(association)	0.350
IL2RA	LTN1	psi-mi:“MI:0914”(association)	0.350
MCUB	GNAI2	psi-mi:“MI:0914”(association)	0.350
ASPH	POTEF	psi-mi:“MI:0914”(association)	0.350
SEC62	IPO8	psi-mi:“MI:0914”(association)	0.350
SLC25A1	CYC1	psi-mi:“MI:0914”(association)	0.350
SLC25A13	CALU	psi-mi:“MI:0914”(association)	0.350
MFSD10	NDUFS8	psi-mi:“MI:0914”(association)	0.350
MFSD5	ILVBL	psi-mi:“MI:0914”(association)	0.350
NIPAL3	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC16A8	C15orf61	psi-mi:“MI:0914”(association)	0.350
SLC27A2	RIMOC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (194): CCDC109B (Affinity Capture-MS), CCDC109B (Affinity Capture-MS), CCDC109B (Affinity Capture-MS), CCDC109B (Affinity Capture-MS), CCDC109B (Affinity Capture-MS), CCDC109B (Affinity Capture-MS), CCDC109B (Affinity Capture-MS), CCDC109B (Affinity Capture-MS), CCDC109B (Affinity Capture-MS), CCDC109B (Affinity Capture-MS), CCDC109B (Affinity Capture-MS), CCDC109B (Affinity Capture-MS), ZBTB16 (Two-hybrid), CCDC109B (Proximity Label-MS), ABCB7 (Proximity Label-MS)

ESM2 similar proteins: A1A4L1, A4QP75, B0S6U7, E1BPN0, E7FCP8, O00142, O55171, P0C1Q3, P19686, P19687, P33402, P49753, P57075, Q02108, Q08CH3, Q1L5Z9, Q1LWG4, Q3B8B2, Q3SZV6, Q3UUI3, Q4V8A1, Q4ZHS0, Q502J0, Q566R0, Q58CX2, Q5IRJ6, Q5R4H0, Q5R8E4, Q5SY16, Q5ZIU8, Q60963, Q63159, Q66GI4, Q6GLK2, Q6PML9, Q6TEC1, Q810S1, Q8BMS4, Q8BWM0, Q8N159

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

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MCUB	“form complex”	MCU_MICUB_variant	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	4
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1508 predictions. Top by Δscore:

Variant	Effect	Δscore
4:109648564:T:TA	donor_gain	1.0000
4:109648565:A:AA	donor_gain	1.0000
4:109659006:TGTA:T	acceptor_loss	1.0000
4:109659007:GTA:G	acceptor_loss	1.0000
4:109659009:A:AG	acceptor_gain	1.0000
4:109659009:AG:A	acceptor_gain	1.0000
4:109659010:G:GA	acceptor_gain	1.0000
4:109659010:GG:G	acceptor_gain	1.0000
4:109659010:GGT:G	acceptor_gain	1.0000
4:109659010:GGTT:G	acceptor_gain	1.0000
4:109659010:GGTTT:G	acceptor_gain	1.0000
4:109659083:GATG:G	donor_gain	1.0000
4:109659084:ATG:A	donor_gain	1.0000
4:109659084:ATGG:A	donor_loss	1.0000
4:109659085:TG:T	donor_gain	1.0000
4:109659085:TGG:T	donor_loss	1.0000
4:109659086:GG:G	donor_gain	1.0000
4:109659086:GGTAA:G	donor_loss	1.0000
4:109659087:G:GG	donor_gain	1.0000
4:109659087:GTA:G	donor_loss	1.0000
4:109659088:T:A	donor_loss	1.0000
4:109660191:ACAG:A	acceptor_loss	1.0000
4:109660192:CAG:C	acceptor_loss	1.0000
4:109660193:A:AG	acceptor_gain	1.0000
4:109660194:G:GG	acceptor_gain	1.0000
4:109660194:GA:G	acceptor_gain	1.0000
4:109660194:GAA:G	acceptor_gain	1.0000
4:109660194:GAAA:G	acceptor_gain	1.0000
4:109660194:GAAAT:G	acceptor_gain	1.0000
4:109660330:A:G	donor_gain	1.0000

AlphaMissense

2207 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:109684565:G:C	W245C	0.988
4:109684565:G:T	W245C	0.988
4:109684563:T:A	W245R	0.978
4:109684563:T:C	W245R	0.978
4:109660269:T:C	F84L	0.977
4:109660271:C:A	F84L	0.977
4:109660271:C:G	F84L	0.977
4:109684582:T:A	V251D	0.971
4:109684577:G:C	E249D	0.963
4:109684577:G:T	E249D	0.963
4:109684537:C:A	A236D	0.959
4:109684629:T:C	F267L	0.956
4:109684631:T:A	F267L	0.956
4:109684631:T:G	F267L	0.956
4:109664343:T:C	F134L	0.955
4:109664345:T:A	F134L	0.955
4:109664345:T:G	F134L	0.955
4:109684624:C:A	A265E	0.954
4:109684548:T:A	W240R	0.950
4:109684548:T:C	W240R	0.950
4:109684567:A:C	D246A	0.950
4:109684626:T:G	Y266D	0.950
4:109660270:T:C	F84S	0.946
4:109684567:A:T	D246V	0.946
4:109684524:G:C	G232R	0.942
4:109684579:C:A	P250Q	0.942
4:109684590:T:C	F254L	0.941
4:109684592:C:A	F254L	0.941
4:109684592:C:G	F254L	0.941
4:109664359:A:T	N139I	0.940

dbSNP variants (sampled 300 via entrez): RS1000027132 (4:109664868 T>C), RS1000050216 (4:109577339 C>T), RS1000053612 (4:109588530 A>C), RS1000126968 (4:109623187 C>T), RS1000127233 (4:109576727 G>A,C), RS1000137943 (4:109664535 C>G), RS1000180350 (4:109559013 T>C), RS1000205720 (4:109598455 G>A,T), RS1000208221 (4:109587921 T>C), RS1000211380 (4:109642029 A>G), RS1000218125 (4:109606934 A>G), RS1000219008 (4:109624738 A>C), RS1000256534 (4:109587378 A>G), RS1000265355 (4:109674579 A>G), RS1000274581 (4:109654119 T>C,G)

Disease associations

OMIM: gene MIM:620702 | 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
GCST010241_149	Apolipoprotein A1 levels	3.000000e-20
GCST010242_335	HDL cholesterol levels	3.000000e-13
GCST010244_309	Triglyceride levels	6.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	4
trichostatin A	decreases expression, affects cotreatment	3
sodium arsenite	affects cotreatment, increases abundance, increases expression, affects expression, decreases expression	3
Cyclosporine	decreases expression, increases expression, increases methylation	3
entinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression	2
GSK-J4	increases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	decreases expression	1
methylparaben	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Vorinostat	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	decreases expression	1
Cadmium	increases expression, increases abundance	1
Carbamazepine	affects expression	1
Cisplatin	increases expression	1
Coumestrol	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Quercetin	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1T7	HAP1 CCDC109B (-) 2	Cancer cell line	Male
CVCL_XM46	HAP1 CCDC109B (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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