MICU3

Summary

MICU3 (mitochondrial calcium uptake 3, HGNC:27820) is a protein-coding gene on chromosome 8p22, encoding Calcium uptake protein 3, mitochondrial (Q86XE3). Tissue-specific calcium sensor of the mitochondrial calcium uniporter (MCU) channel, which specifically regulates MCU channel activity in the central nervous system and skeletal muscle.

Enables calcium channel regulator activity; calcium ion sensor activity; and protein heterodimerization activity. Involved in calcium import into the mitochondrion and cellular response to calcium ion. Located in mitochondrion.

Source: NCBI Gene 286097 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 91 total
• MANE Select transcript: NM_181723

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27820
Approved symbol	MICU3
Name	mitochondrial calcium uptake 3
Location	8p22
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp313A0139
Ensembl gene	ENSG00000155970
Ensembl biotype	protein_coding
OMIM	610633
Entrez	286097

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 15 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000318063, ENST00000517398, ENST00000517447, ENST00000519044, ENST00000519866, ENST00000522235, ENST00000908133, ENST00000908134, ENST00000908135, ENST00000920037, ENST00000920038, ENST00000952686, ENST00000952687, ENST00000952688, ENST00000952689, ENST00000952690, ENST00000952691, ENST00000952692

RefSeq mRNA: 11 — MANE Select: NM_181723 NM_001349810, NM_001413217, NM_001413218, NM_001413219, NM_001413221, NM_001413222, NM_001413223, NM_001413224, NM_001413225, NM_001413226, NM_181723

CCDS: CCDS5999

Canonical transcript exons

ENST00000318063 — 15 exons

Exon	Start	End
ENSE00001023680	17116443	17116600
ENSE00001023688	17114093	17114201
ENSE00001277512	17105413	17105584
ENSE00001277566	17118707	17118775
ENSE00001295630	17090546	17090584
ENSE00001305528	17120288	17122642
ENSE00001321008	17098458	17098553
ENSE00001325708	17027238	17027660
ENSE00003463537	17077783	17077861
ENSE00003488630	17064084	17064237
ENSE00003504037	17086964	17087035
ENSE00003533986	17081693	17081740
ENSE00003598860	17104391	17104491
ENSE00003660868	17085236	17085318
ENSE00003688382	17069688	17069719

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 97.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.8187 / max 203.9290, expressed in 1382 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87519	9.7648	1382
87520	0.0539	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	97.56	gold quality
endothelial cell	CL:0000115	97.43	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.33	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.31	gold quality
adrenal tissue	UBERON:0018303	94.69	gold quality
primary visual cortex	UBERON:0002436	94.67	gold quality
calcaneal tendon	UBERON:0003701	94.55	gold quality
occipital lobe	UBERON:0002021	93.83	gold quality
superior frontal gyrus	UBERON:0002661	93.40	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.40	gold quality
postcentral gyrus	UBERON:0002581	93.00	gold quality
parietal lobe	UBERON:0001872	92.47	gold quality
entorhinal cortex	UBERON:0002728	91.69	gold quality
cerebellar cortex	UBERON:0002129	91.48	gold quality
cerebellum	UBERON:0002037	91.47	gold quality
cerebellar hemisphere	UBERON:0002245	91.38	gold quality
prefrontal cortex	UBERON:0000451	90.88	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.78	gold quality
pons	UBERON:0000988	90.61	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	90.43	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.24	gold quality
frontal cortex	UBERON:0001870	89.70	gold quality
cerebral cortex	UBERON:0000956	89.36	gold quality
neocortex	UBERON:0001950	89.25	gold quality
substantia nigra pars compacta	UBERON:0001965	89.13	gold quality
lateral globus pallidus	UBERON:0002476	88.99	gold quality
corpus callosum	UBERON:0002336	88.52	gold quality
dorsal root ganglion	UBERON:0000044	88.09	gold quality
popliteal artery	UBERON:0002250	87.88	gold quality
tibial artery	UBERON:0007610	87.87	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

178 targeting MICU3, 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-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4723-5P	99.97	68.70	2034

Literature-anchored findings (GeneRIF, showing 2)

• multiple crystal structures of MICU2 and MICU3 from Homo sapiens, were determined. (PMID:30699349)
• MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy. (PMID:38747181)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	micu3b	ENSDARG00000074255
danio_rerio	micu3a	ENSDARG00000078599
mus_musculus	Micu3	ENSMUSG00000039478
rattus_norvegicus	Micu3	ENSRNOG00000012767
drosophila_melanogaster	MICU3	FBGN0038735
caenorhabditis_elegans		WBGENE00008345

Paralogs (2): MICU1 (ENSG00000107745), MICU2 (ENSG00000165487)

Protein

Protein identifiers

Calcium uptake protein 3, mitochondrial — Q86XE3 (reviewed: Q86XE3)

Alternative names: EF-hand domain-containing family member A2

All UniProt accessions (3): Q86XE3, H0YAN7, H0YB82

UniProt curated annotations — full annotation on UniProt →

Function. Tissue-specific calcium sensor of the mitochondrial calcium uniporter (MCU) channel, which specifically regulates MCU channel activity in the central nervous system and skeletal muscle. Senses calcium level via its EF-hand domains: compared to MICU1 and MICU2, MICU3 has a higher affinity for calcium. MICU1 and MICU3 form a disulfide-linked heterodimer that stimulates and inhibits MCU activity, depending on the concentration of calcium. 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 MICU3 induces a conformational change that weakens MCU-MICU1 interactions and moves the MICU1-MICU3 heterodimer away from the pore, allowing calcium permeation through the MCU channel. The high calcium affinity of MICU3 lowers the calcium threshold necessary for calcium permeation through the MCU channel. The MICU1-MICU3 heterodimer promotes flexibility of neurotransmission in neuronal cells by enhancing mitochondrial calcium uptake in presynapses. It is also required to increase mitochondrial calcium uptake in skeletal muscle cells, thereby increasing ATP production.

Subunit / interactions. Heterodimer; disulfide-linked; heterodimerizes with MICU1. Component of the uniplex complex, composed of MCU, EMRE/SMDT1, MICU1 and MICU3 in a 4:4:1:1 stoichiometry.

Subcellular location. Mitochondrion intermembrane space. Mitochondrion inner membrane.

Tissue specificity. Specifically expressed in the central nervous system and skeletal muscle.

Domain organisation. EF-hand domains 1 and 3 have high affinity for calcium and act as sensors of mitochondrial matrix calcium levels. EF-hand domain 2 is degenerate.

Similarity. Belongs to the MICU1 family. MICU3 subfamily.

RefSeq proteins (11): NP_001336739, NP_001400146, NP_001400147, NP_001400148, NP_001400150, NP_001400151, NP_001400152, NP_001400153, NP_001400154, NP_001400155, NP_859074* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR039800	MICU1/2/3	Family

Pfam: PF13499

UniProt features (52 total): helix 19, binding site 11, strand 7, mutagenesis site 5, domain 3, turn 2, transit peptide 1, chain 1, disulfide bond 1, sequence conflict 1, region of interest 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6AGI	X-RAY DIFFRACTION	2.8
6AGJ	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86XE3-F1	72.34	0.35

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 (11): 253; 256; 483; 485; 487; 489; 494; 245; 247; 249; 251

Disulfide bonds (1): 522

Mutagenesis-validated functional residues (5):

Position	Phenotype
245	in ef1(mut); abolished calcium-binding; when associated with k-256, a-483 and k-494.
256	in ef1(mut); abolished calcium-binding; when associated with a-245, a-483 and k-494.
483	in ef1(mut); abolished calcium-binding; when associated with a-245, k-256 and k-494.
494	in ef1(mut); abolished calcium-binding; when associated with a-245, k-256 and a-483.
522	abolished interaction with micu1.

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: 163 (showing top): GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_RESPONSE_TO_METAL_ION, GOBP_MITOCHONDRIAL_CALCIUM_ION_HOMEOSTASIS, WONG_ENDMETRIUM_CANCER_DN, GOBP_REGULATION_OF_NEUROTRANSMITTER_TRANSPORT, GOBP_SECRETION, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_POSITIVE_REGULATION_OF_NEUROTRANSMITTER_SECRETION, GOBP_SIGNAL_RELEASE, GOBP_SYNAPTIC_SIGNALING, GOBP_POSITIVE_REGULATION_OF_NEUROTRANSMITTER_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_CALCIUM_ION, GOBP_MONOATOMIC_ION_HOMEOSTASIS

GO Biological Process (5): positive regulation of neurotransmitter secretion (GO:0001956), calcium import into the mitochondrion (GO:0036444), mitochondrial calcium ion homeostasis (GO:0051560), cellular response to calcium ion (GO:0071277), mitochondrial calcium ion transmembrane transport (GO:0006851)

GO Molecular Function (5): calcium channel regulator activity (GO:0005246), calcium ion binding (GO:0005509), protein heterodimerization activity (GO:0046982), calcium ion sensor activity (GO:0061891), metal ion binding (GO:0046872)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial intermembrane space (GO:0005758), 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
neurotransmitter secretion	1
regulation of neurotransmitter secretion	1
positive regulation of synaptic transmission	1
positive regulation of neurotransmitter transport	1
positive regulation of secretion by cell	1
mitochondrial calcium ion transmembrane transport	1
intercellular transport	1
mitochondrion	1
intracellular calcium ion homeostasis	1
response to calcium ion	1
cellular response to metal ion	1
calcium ion transmembrane transport	1
calcium channel activity	1
ion channel regulator activity	1
metal ion binding	1
protein dimerization activity	1
calcium ion binding	1
metal ion sensor activity	1
cation binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrial envelope	1
organelle envelope lumen	1
calcium channel complex	1
inner mitochondrial membrane protein complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

618 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MICU3	SMDT1	Q9H4I9	993
MICU3	MCUR1	Q96AQ8	992
MICU3	MCUB	Q9NWR8	989
MICU3	MICU2	Q8IYU8	973
MICU3	MICU1	Q9BPX6	973
MICU3	MCU	Q8NE86	900
MICU3	FGF20	Q9NP95	770
MICU3	FGF9	P31371	762
MICU3	SLC25A23	Q9BV35	729
MICU3	SLC8B1	Q6J4K2	667
MICU3	VDAC1	P21796	619
MICU3	HSPA9	P30036	535
MICU3	LETM1	O95202	530
MICU3	MFN2	O95140	520
MICU3	SIGMAR1	Q99720	511

IntAct

8 interactions, top by confidence:

A	B	Type	Score
THUMPD3	TRMU	psi-mi:“MI:0914”(association)	0.350
MICU1	MICU3	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
MICU3	SERPINA1	psi-mi:“MI:0914”(association)	0.350

BioGRID (17): MICU3 (Biochemical Activity), MICU3 (Affinity Capture-MS), MICU3 (Affinity Capture-MS), MICU3 (Affinity Capture-MS), MICU3 (Proximity Label-MS), IGHM (Affinity Capture-MS), IGHG1 (Affinity Capture-MS), PLBD1 (Affinity Capture-MS), MICU3 (Affinity Capture-MS), SERPINA1 (Affinity Capture-MS), PKP1 (Affinity Capture-MS), MICU3 (Affinity Capture-MS), DBT (Affinity Capture-MS), ALB (Affinity Capture-MS), SERPINB2 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I6A2H6, A2VEI2, A4IG32, A4IHK8, A5D7A0, D2HZB0, D4A1F2, E9Q4Z2, F1MF74, O00763, O08874, O14795, O94851, P23092, Q05AA6, Q08BI9, Q13474, Q17QM6, Q3TWN3, Q4FZY0, Q4KUS2, Q4V8B2, Q5E9V1, Q5R9G1, Q5RDI4, Q5U2P1, Q5ZJT0, Q62768, Q62769, Q69ZT9, Q6DFA1, Q86XE3, Q8BHD4, Q8BML1, Q8IWE4, Q8K0V2, Q8WN03, Q96C19, Q9BQI0, Q9BUP0

Diamond homologs: A0A8I6A2H6, Q86XE3, Q8CD10, Q8IYU8, Q99P63, Q9CTY5, A8WQT4, Q95PZ2, Q9SZ45, F1LX07

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MICU3	“form complex”	MCU_MICU3_variant	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	73
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3387 predictions. Top by Δscore:

Variant	Effect	Δscore
8:17064233:CAAAG:C	donor_gain	1.0000
8:17064234:AAAG:A	donor_gain	1.0000
8:17064235:AAG:A	donor_gain	1.0000
8:17064235:AAGGT:A	donor_loss	1.0000
8:17064236:AG:A	donor_gain	1.0000
8:17064236:AGGT:A	donor_loss	1.0000
8:17064237:GG:G	donor_gain	1.0000
8:17064237:GGTA:G	donor_loss	1.0000
8:17064238:G:GG	donor_gain	1.0000
8:17064238:GTAA:G	donor_loss	1.0000
8:17069686:A:AG	acceptor_gain	1.0000
8:17069687:G:GG	acceptor_gain	1.0000
8:17085317:TGG:T	donor_loss	1.0000
8:17085320:T:A	donor_loss	1.0000
8:17086962:A:AG	acceptor_gain	1.0000
8:17086963:G:GG	acceptor_gain	1.0000
8:17090490:ACTTG:A	acceptor_gain	1.0000
8:17102302:GATAA:G	donor_gain	1.0000
8:17102310:G:GG	donor_gain	1.0000
8:17104388:A:AG	acceptor_gain	1.0000
8:17104388:AAGC:A	acceptor_gain	1.0000
8:17104389:A:AG	acceptor_gain	1.0000
8:17104389:AGC:A	acceptor_gain	1.0000
8:17104389:AGCGT:A	acceptor_gain	1.0000
8:17104390:G:GA	acceptor_gain	1.0000
8:17104390:GC:G	acceptor_gain	1.0000
8:17104390:GCG:G	acceptor_gain	1.0000
8:17104390:GCGT:G	acceptor_gain	1.0000
8:17104390:GCGTG:G	acceptor_gain	1.0000
8:17104488:ATAG:A	donor_loss	1.0000

AlphaMissense

3464 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:17081723:T:C	L226P	1.000
8:17085260:C:A	A240D	1.000
8:17085262:T:C	F241L	1.000
8:17085263:T:C	F241S	1.000
8:17085264:C:A	F241L	1.000
8:17085264:C:G	F241L	1.000
8:17085272:T:C	F244S	1.000
8:17085274:G:C	D245H	1.000
8:17085275:A:C	D245A	1.000
8:17085275:A:G	D245G	1.000
8:17085275:A:T	D245V	1.000
8:17085276:C:A	D245E	1.000
8:17085276:C:G	D245E	1.000
8:17085296:T:A	V252E	1.000
8:17085308:A:T	E256V	1.000
8:17085310:T:C	F257L	1.000
8:17085311:T:C	F257S	1.000
8:17085312:T:A	F257L	1.000
8:17085312:T:G	F257L	1.000
8:17104439:C:G	H345D	1.000
8:17104445:T:C	F347L	1.000
8:17104447:T:A	F347L	1.000
8:17104447:T:G	F347L	1.000
8:17104470:T:A	L355H	1.000
8:17104470:T:C	L355P	1.000
8:17105427:T:C	L367P	1.000
8:17105453:T:C	F376L	1.000
8:17105454:T:C	F376S	1.000
8:17105455:C:A	F376L	1.000
8:17105455:C:G	F376L	1.000

dbSNP variants (sampled 300 via entrez): RS1000004048 (8:17079075 A>T), RS1000042305 (8:17087028 C>A,T), RS1000089830 (8:17110792 G>T), RS1000118376 (8:17079243 A>C,G), RS1000127558 (8:17035345 T>C), RS1000129869 (8:17124055 A>G), RS1000135367 (8:17097214 C>G,T), RS1000148388 (8:17044919 A>G), RS1000179224 (8:17067703 G>A), RS1000186606 (8:17118754 G>A), RS1000199536 (8:17102848 A>G), RS1000202644 (8:17057415 T>C), RS1000294024 (8:17073936 A>G), RS1000316053 (8:17089634 T>C,G), RS1000321328 (8:17119044 A>G,T)

Disease associations

OMIM: gene MIM:610633 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001313_7	Depression and alcohol dependence	8.000000e-06
GCST004902_1	Parkinson’s disease	2.000000e-11

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	decreases expression, increases expression, affects cotreatment	3
Tetrachlorodibenzodioxin	affects expression, decreases expression	3
bisphenol A	increases methylation, affects cotreatment, decreases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Nickel	decreases expression	2
Valproic Acid	decreases methylation, increases expression	2
terbufos	increases methylation	1
arsenite	affects binding, decreases reaction	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	increases reaction, affects binding	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Leflunomide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cadmium	increases abundance, increases expression	1
Cisplatin	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Fonofos	increases methylation	1
Indomethacin	affects cotreatment, decreases expression	1
Parathion	increases methylation	1
Tobacco Smoke Pollution	decreases expression	1

Clinical trials (associated diseases)

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