MICU1

Summary

MICU1 (mitochondrial calcium uptake 1, HGNC:1530) is a protein-coding gene on chromosome 10q22.1, encoding Calcium uptake protein 1, mitochondrial (Q9BPX6). Calcium sensor of the mitochondrial calcium uniporter (MCU) channel, which senses calcium level via its EF-hand domains.

This gene encodes an essential regulator of mitochondrial Ca2+ uptake under basal conditions. The encoded protein interacts with the mitochondrial calcium uniporter, a mitochondrial inner membrane Ca2+ channel, and is essential in preventing mitochondrial Ca2+ overload, which can cause excessive production of reactive oxygen species and cell stress. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 10367 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 360 total — 33 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 67
• MANE Select transcript: NM_001195518

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1530
Approved symbol	MICU1
Name	mitochondrial calcium uptake 1
Location	10q22.1
Locus type	gene with protein product
Status	Approved
Aliases	CALC, EFHA3, FLJ12684
Ensembl gene	ENSG00000107745
Ensembl biotype	protein_coding
OMIM	605084
Entrez	10367

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 33 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000361114, ENST00000398763, ENST00000418483, ENST00000476605, ENST00000489666, ENST00000603011, ENST00000604025, ENST00000604238, ENST00000604529, ENST00000635239, ENST00000642044, ENST00000897972, ENST00000897973, ENST00000897974, ENST00000897975, ENST00000897976, ENST00000897977, ENST00000897978, ENST00000897979, ENST00000897980, ENST00000897981, ENST00000897982, ENST00000897983, ENST00000897984, ENST00000897985, ENST00000897986, ENST00000897987, ENST00000964203, ENST00000964204, ENST00000964205, ENST00000964206, ENST00000964207, ENST00000964208, ENST00000964209, ENST00000964210, ENST00000964211

RefSeq mRNA: 4 — MANE Select: NM_001195518 NM_001195518, NM_001195519, NM_001363513, NM_006077

CCDS: CCDS55714, CCDS55715, CCDS86101

Canonical transcript exons

ENST00000361114 — 12 exons

Exon	Start	End
ENSE00001402573	72626010	72626079
ENSE00001600852	72562895	72563063
ENSE00001665451	72533746	72533789
ENSE00001719942	72551179	72551341
ENSE00003515063	72566633	72566794
ENSE00003521511	72508155	72508269
ENSE00003568362	72475100	72475297
ENSE00003574028	72477174	72477256
ENSE00003606319	72407929	72408037
ENSE00003612065	72423234	72423371
ENSE00003629540	72367340	72368355
ENSE00003651748	72375783	72375872

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 98.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 48.2682 / max 1220.0572, expressed in 1822 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110013	43.1405	1822
110014	4.0062	1594
110012	1.0564	501
110009	0.0650	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.09	gold quality
cerebellar hemisphere	UBERON:0002245	97.74	gold quality
cerebellar cortex	UBERON:0002129	97.64	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.62	gold quality
cerebellum	UBERON:0002037	97.01	gold quality
adrenal tissue	UBERON:0018303	96.50	gold quality
right adrenal gland cortex	UBERON:0035827	96.17	gold quality
monocyte	CL:0000576	96.11	gold quality
right adrenal gland	UBERON:0001233	96.02	gold quality
mononuclear cell	CL:0000842	95.87	gold quality
leukocyte	CL:0000738	95.59	gold quality
left adrenal gland	UBERON:0001234	95.39	gold quality
muscle of leg	UBERON:0001383	95.25	gold quality
right frontal lobe	UBERON:0002810	95.24	gold quality
gastrocnemius	UBERON:0001388	95.16	gold quality
left adrenal gland cortex	UBERON:0035825	95.03	gold quality
cortical plate	UBERON:0005343	95.02	gold quality
adrenal gland	UBERON:0002369	94.98	gold quality
prefrontal cortex	UBERON:0000451	94.73	gold quality
ganglionic eminence	UBERON:0004023	94.69	gold quality
adrenal cortex	UBERON:0001235	94.46	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.29	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.14	gold quality
cingulate cortex	UBERON:0003027	94.04	gold quality
right lobe of liver	UBERON:0001114	94.02	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.99	gold quality
anterior cingulate cortex	UBERON:0009835	93.96	gold quality
ventricular zone	UBERON:0003053	93.92	gold quality
muscle organ	UBERON:0001630	93.89	gold quality
smooth muscle tissue	UBERON:0001135	93.76	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.74

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): JUN

miRNA regulators (miRDB)

55 targeting MICU1, 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-548P	99.98	72.25	3784
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-5197-5P	99.64	69.08	1494
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-7849-3P	99.47	68.17	1224
HSA-MIR-1206	99.30	69.32	1016
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-4705	99.10	69.10	1091
HSA-MIR-3145-3P	98.85	69.07	2031
HSA-MIR-487A-5P	98.85	69.37	993
HSA-MIR-487B-5P	98.85	69.48	987

Literature-anchored findings (GeneRIF, showing 38)

• MICU1 (CBARA1) is an EF-hand containing protein associated with the mitochondrial inner membrane. It is required for mitochondrial calcium uptake in HeLa cells. (PMID:20693986)
• MICU1 represents the founding member of a set of proteins required for high-capacity mitochondrial calcium uptake (PMID:20693986)
• MICU1 physically interacts with MCU, a principal component of the mitochondrial calcium uniporter. (PMID:21685886)
• 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)
• MICU1 is a gatekeeper of mitochondrial calcium uniporter-mediated Ca(2 )uptake that is essential to prevent [Ca(2 )]overload and associated stress. (PMID:23101630)
• MICU1 is a novel regulator of the machinery in cancer cells that prevents apoptosis. (PMID:23615904)
• CBARA1 is a marker for undifferentiated human embryonic stem cells that plays a role in maintaining stemness, cell cycle progression, and proliferation. (PMID:23667653)
• Prolonged MICU1 loss leads to an adaptive increase in matrix Ca(2+) binding, yet cells show impaired oxidative metabolism and sensitization to Ca(2+) overload. (PMID:23747253)
• MICU1 EF hands determine MCU activity, but not binding. (PMID:24332854)
• Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. (PMID:24336167)
• Expression of MICU1 mutants lacking functional Ca2+-binding sites leads to a striking loss of Ca2+ uptake in HEK293 cells. (PMID:24503055)
• MICU1 and MICU2 have roles in tuning the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity (PMID:24560927)
• Loss of heterozygosity of MICU1 gene on chromosome 10q is associated with pancreatic cancer. (PMID:25824785)
• Data show that ribosomal protein S3 (RPS3) knockdown decreased mitochondrial calcium uptake 1 protein (MICU1) expression. (PMID:26336993)
• 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)
• Results showed that the SNP on EF-hand Ca2+ binding domains of MICU1 gene had no effect in phenotypic characters of bipolar disorder patients (PMID:27297032)
• 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)
• MICU1 serves as a signal-noise discriminator in mitochondrial calcium signalling, limiting the energetic costs of mitochondrial Ca2+ signalling which may undermine oxidative phosphorylation, especially in tissues with highly dynamic energetic demands. (PMID:28132899)
• drives aberrant metabolism that fuels aerobic glycolysis and chemoresistance in ovarian cancer (PMID:28530221)
• study concludes that cooperative, high-affinity interaction of the MICU1-MICU2 complex with Ca(2+) serves as an on-off switch, leading to a tightly controlled channel, capable of responding directly to cytosolic Ca(2+) signals (PMID:28615291)
• MICU2 restricts spatial crosstalk between InsP3R and MCU channels by regulating threshold and gain of MICU1-mediated inhibition and activation of MCU. (PMID:29241542)
• the absence of MICU1, both Mn(2+) and Ca(2+) can pass through the uniporter, as evidenced by mitochondrial Mn(2+) uptake assays, mitochondrial membrane potential measurements, and mitoplast electrophysiology. (PMID:30082385)
• FOXD1-dependent MICU1 expression regulates mitochondrial activity and cell differentiation (PMID:30158529)
• MICU1 deletion sensitizes human cells to manganese-dependent cell death by disinhibiting MCU-mediated manganese uptake. (PMID:30403999)
• Authors propose that MICU1 has to interact with the D-ring formed by the DIME domains in MCU to control the uniporter. (PMID:30454562)
• Data show that phosphorylation at the N-terminal region of MICU1 leads to an increase in the basal mitochondrial Ca(2+) levels. A pool of active Akt in the mitochondria is responsible for MICU1 phosphorylation, and mitochondrion-targeted Akt strongly regulates the mitochondrial Ca(2+). The Akt-mediated phosphorylation impairs MICU1 processing and stability, culminating in ROS production and tumor progression. (PMID:30504268)
• MICU1 confers Ca(2+)-dependent gating of the uniporter by blocking/unblocking MCU. (PMID:30638448)
• The findings unveil an essential function of MICU1 in cristae junction stabilization and provide mechanistic insights of how sophistically MICU1 controls the mitochondrial calcium uniporter-Complex while maintaining the structural mitochondrial membrane framework. (PMID:31427612)
• Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1. (PMID:31665639)
• Mitochondrial pyruvate and fatty acid flux modulate MICU1-dependent control of MCU activity. (PMID:32317369)
• Structures reveal gatekeeping of the mitochondrial Ca(2+) uniporter by MICU1-MICU2. (PMID:32667285)
• The structure of the MICU1-MICU2 complex unveils the regulation of the mitochondrial calcium uniporter. (PMID:32790952)
• Mechanisms of EMRE-Dependent MCU Opening in the Mitochondrial Calcium Uniporter Complex. (PMID:33296646)
• Molecular pathophysiology of human MICU1 deficiency. (PMID:33428302)
• The Splicing of the Mitochondrial Calcium Uniporter Genuine Activator MICU1 Is Driven by RBFOX2 Splicing Factor during Myogenic Differentiation. (PMID:35269658)
• Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients. (PMID:35302860)
• Mechanisms and significance of tissue-specific MICU regulation of the mitochondrial calcium uniporter complex. (PMID:36206740)
• MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart. (PMID:39163336)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	micu1	ENSDARG00000063358
mus_musculus	Micu1	ENSMUSG00000020111
rattus_norvegicus	Micu1	ENSRNOG00000043436
drosophila_melanogaster	MICU1	FBGN0031893
caenorhabditis_elegans		WBGENE00013462

Paralogs (2): MICU3 (ENSG00000155970), MICU2 (ENSG00000165487)

Protein

Protein identifiers

Calcium uptake protein 1, mitochondrial — Q9BPX6 (reviewed: Q9BPX6)

Alternative names: Atopy-related autoantigen CALC, Calcium-binding atopy-related autoantigen 1

All UniProt accessions (6): Q9BPX6, A0A286YF11, E9PQV6, S4R3D7, S4R3V1, S4R3W3

UniProt curated annotations — full annotation on UniProt →

Function. Calcium sensor of the mitochondrial calcium uniporter (MCU) channel, which senses calcium level via its EF-hand domains. MICU1 and MICU2 (or 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 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 MCU channel. Also required to protect against manganese toxicity by preventing manganese uptake by MCU: mechanistically, manganese-binding to its EF-hand domains does not induce any conformational change, maintaining MCU pore occlusion. Also acts as a barrier for inhibitors of the MCU channel, such as ruthenium red or its derivative Ru360. Acts as a regulator of mitochondrial cristae structure independently of its ability to regulate the mitochondrial calcium uniporter channel. Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake. Induces T-helper 1-mediated autoreactivity, which is accompanied by the release of IFNG. Isoform that regulates mitochondrial calcium uniporter (MCU) in the skeletal muscle. Compared to other isoforms, this isoform has higher affinity for calcium, promoting mitochondrial calcium uptake at lower calcium concentrations. This allows a rapid response of mitochondrial metabolism and ensures sustained ATP production needed for resistance and strenuous exercise.

Subunit / interactions. Heterodimer; disulfide-linked; heterodimerizes with MICU2 or MICU3. Homodimer; disulfide-linked. Component of the uniplex complex, composed of MCU, EMRE/SMDT1, MICU1 and MICU2 (or MICU3) in a 4:4:1:1 stoichiometry. The composition of calcium sensors within the uniplex complex can differ depending on tissues: a MICU1 homodimer can be present instead of the MICU1-MICU2 heterodimer in skeletal-muscle and kidney. MICU1 is recruited to the uniplex complex by EMRE/SMDT1, and it associates with MCU at low calcium levels, occluding the pore of the MCU channel. Associates with the MICOS complex. Interacts with SLC25A23. Interacts with CHCHD4/MIA40; which introduces the interchain disulfide bond with MICU2. Interacts (when methylated) with UCP2; leading to decrease the calcium sensitivity of MICU1.

Subcellular location. Mitochondrion intermembrane space. Mitochondrion inner membrane Mitochondrion intermembrane space. Mitochondrion inner membrane.

Tissue specificity. Expressed in epithelial cell lines. Strongly expressed in epidermal keratinocytes and dermal endothelial cells.

Post-translational modifications. Phosphorylation at Ser-122 by AKT1 impairs its maturation and stability. Asymmetric dimethylation at Arg-455 by PRMT1 decreases the calcium sensitivity of MICU1 by promoting interaction with UCP2. Degraded by YME1L1 when not complexed as homodimer or heterodimer. Not degraded when complexed as homodimer or heterodimer; the presence of the interchain disulfide bond protecting MICU1 from degradation by YME1L1.

Disease relevance. Myopathy with extrapyramidal signs (MPXPS) [MIM:615673] An autosomal recessive disorder characterized by early-onset proximal muscle weakness with a static course and moderately to grossly elevated serum creatine kinase levels accompanied by learning difficulties. Most patients develop subtle extrapyramidal motor signs that progress to a debilitating disorder of involuntary movement with variable features, including chorea, tremor, dystonic posturing and orofacial dyskinesia. Additional variable features include ataxia, microcephaly, ophthalmoplegia, ptosis, optic atrophy and axonal peripheral neuropathy. The disease is caused by variants affecting the gene represented in this entry. The complex phenotype is due to alterations in mitochondrial calcium signaling characterized by increased mitochondrial Ca(2+) load. An homozygous partial MICU1 deletion is responsible for a disorder manifesting in childhood with fatigue, lethargy and muscle weakness. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by spermine, kaempferol and SB202190, which bind MICU1 and prevent MCU pore occlusion in absence of calcium.

Domain organisation. The EF-hand domains have high affinity for calcium and act as sensors of calcium levels. The polybasic region mediates interaction with EMRE/SMDT1 and association with the uniplex complex. Lysine and arginine residues in the K/R-ring mediate electrostatic interactions with MCU and play a key role in MCU inhibition in absence of calcium. The C-helix plays a key role in mitochondrial calcium uptake, probably by mediating interaction with MICU2.

Similarity. Belongs to the MICU1 family. MICU1 subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
Q9BPX6-1	1	yes
Q9BPX6-2	2
Q9BPX6-3	3
Q9BPX6-4	4
Q9BPX6-5	5
Q9BPX6-6	6, MICU1.1

RefSeq proteins (4): NP_001182447, NP_001182448, NP_001350442, NP_006068 (=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: PF13202, PF13833

UniProt features (101 total): mutagenesis site 31, helix 20, binding site 10, strand 10, splice variant 7, region of interest 5, turn 5, sequence variant 4, modified residue 2, domain 2, sequence conflict 2, transit peptide 1, chain 1, disulfide bond 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
6LB7	X-RAY DIFFRACTION	2.1
4NSD	X-RAY DIFFRACTION	2.7
6LE5	X-RAY DIFFRACTION	3.1
6XQO	ELECTRON MICROSCOPY	3.1
4NSC	X-RAY DIFFRACTION	3.2
6WDN	ELECTRON MICROSCOPY	3.2
6LB8	X-RAY DIFFRACTION	3.28
6XQN	ELECTRON MICROSCOPY	3.3
6K7Y	ELECTRON MICROSCOPY	3.6
6WDO	ELECTRON MICROSCOPY	3.6
6XJV	ELECTRON MICROSCOPY	4.17
6XJX	ELECTRON MICROSCOPY	4.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BPX6-F1	76.82	0.45

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 (10): 233; 235; 237; 242; 421; 423; 425; 427; 432; 231

Post-translational modifications (2): 122, 455

Disulfide bonds (1): 463

Mutagenesis-validated functional residues (31):

Position	Phenotype
99–103	abolishes interaction with emre/smdt1.
99–102	abolishes interaction with emre/smdt1 while maintaining interaction with micu2.
106	slightly decreased ability to inhibit mcu channel activity in absence of calcium.
114	decreased ability to inhibit mcu channel activity in absence of calcium.
117	slightly decreased ability to inhibit mcu channel activity in absence of calcium.
119	impaired interaction with mcu.
119	does not affect interaction with mcu.
121	decreased ability to inhibit mcu channel activity in absence of calcium.
126–129	abolished ability to inhibit mcu channel activity in absence of calcium; when associated with 259-e–e-263.
126	abolished ability to inhibit mcu channel activity in absence of calcium.
126	abolished ability to inhibit mcu in absence of calcium.
129	decreased ability to inhibit mcu channel activity in absence of calcium.
154	does not affect interaction with mcu.
154	impaired interaction with mcu.
221	abolishes homooligomerization.
231	abolishes mitochondrial ca(2+) uptake; when associated with a-242; a-421 and a-432.
242	abolishes mitochondrial ca(2+) uptake; when associated with a-231; a-421 and a-432.
253	does not affect interaction with micu2 in presence of calcium; decreased interaction with micu2 in absence of calcium.
259–263	abolished ability to inhibit mcu channel activity in absence of calcium; when associated with 126-e–e-129.
376	abolishes homooligomerization.
383–385	abolishes homooligomerization.
383	abolished interaction with micu2.
398	does not affect interaction with micu2 in absence or presence of calcium.
421	abolishes mitochondrial ca(2+) uptake; when associated with a-231; a-242 and a-432.
427	does not affect interaction with micu2 in presence of calcium; decreased interaction with micu2 in absence of calcium.

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: 337 (showing top): RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_HYPEROSMOTIC_RESPONSE, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_CRISTAE_FORMATION, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_RESPONSE_TO_METAL_ION, GOBP_MITOCHONDRIAL_CALCIUM_ION_HOMEOSTASIS, CAIRO_HEPATOBLASTOMA_CLASSES_DN, GOBP_REGULATION_OF_MITOCHONDRION_ORGANIZATION, GOBP_CALCIUM_ION_IMPORT, GOBP_INNER_MITOCHONDRIAL_MEMBRANE_ORGANIZATION, GOBP_RESPONSE_TO_SALT_STRESS, IRF1_Q6

GO Biological Process (13): mitochondrial calcium ion transmembrane transport (GO:0006851), defense response (GO:0006952), calcium import into the mitochondrion (GO:0036444), protein homooligomerization (GO:0051260), mitochondrial calcium ion homeostasis (GO:0051560), positive regulation of mitochondrial calcium ion concentration (GO:0051561), calcium ion import (GO:0070509), cellular response to calcium ion (GO:0071277), cellular response to calcium ion starvation (GO:0072732), regulation of cellular hyperosmotic salinity response (GO:1900069), positive regulation of cristae formation (GO:1903852), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816)

GO Molecular Function (8): calcium ion binding (GO:0005509), calcium channel inhibitor activity (GO:0019855), identical protein binding (GO:0042802), protein heterodimerization activity (GO:0046982), calcium ion sensor activity (GO:0061891), calcium channel regulator activity (GO:0005246), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (8): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial intermembrane space (GO:0005758), mitochondrial membrane (GO:0031966), calcium channel complex (GO:0034704), mitochondrial crista junction (GO:0044284), 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
mitochondrion	2
calcium channel activity	2
mitochondrial envelope	2
calcium ion transmembrane transport	1
response to stress	1
mitochondrial calcium ion transmembrane transport	1
intercellular transport	1
protein complex oligomerization	1
intracellular calcium ion homeostasis	1
mitochondrial calcium ion homeostasis	1
calcium ion transport	1
response to calcium ion	1
cellular response to metal ion	1
cellular response to starvation	1
cellular hyperosmotic salinity response	1
regulation of cellular response to osmotic stress	1
regulation of response to salt stress	1
positive regulation of organelle organization	1
cristae formation	1
regulation of cristae formation	1
transport	1
metal ion transport	1
metal ion binding	1
calcium channel regulator activity	1
ion channel inhibitor activity	1
protein binding	1
protein dimerization activity	1
calcium ion binding	1
metal ion sensor activity	1
ion channel regulator activity	1
binding	1
cation binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
organelle envelope lumen	1
organelle membrane	1
cation channel complex	1
mitochondrial inner membrane	1

Protein interactions and networks

STRING

1030 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MICU1	SMDT1	Q9H4I9	999
MICU1	MCUB	Q9NWR8	998
MICU1	MCUR1	Q96AQ8	997
MICU1	MCU	Q8NE86	996
MICU1	MICU2	Q8IYU8	988
MICU1	SLC25A23	Q9BV35	985
MICU1	MICU3	Q86XE3	973
MICU1	CHCHD4	Q8N4Q1	886
MICU1	LETM1	O95202	838
MICU1	SLC8B1	Q6J4K2	806
MICU1	VDAC1	P21796	787
MICU1	LDHA	P00338	781
MICU1	UCP2	P55851	778
MICU1	ITPR3	Q14573	769
MICU1	ITPR1	Q14643	767

IntAct

98 interactions, top by confidence:

A	B	Type	Score
MICU2	MICU1	psi-mi:“MI:0915”(physical association)	0.780
MICU1	MICU2	psi-mi:“MI:0914”(association)	0.780
MICU1	MICU2	psi-mi:“MI:0915”(physical association)	0.780
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
CHCHD4	SSNA1	psi-mi:“MI:0914”(association)	0.640
KLHL22	TMEM223	psi-mi:“MI:0914”(association)	0.640
TUBA1B	TXNDC9	psi-mi:“MI:0914”(association)	0.640
KLHL22	METTL15	psi-mi:“MI:0914”(association)	0.640
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
MCU	MICU1	psi-mi:“MI:0915”(physical association)	0.590
CHCHD4	MICU1	psi-mi:“MI:0915”(physical association)	0.580
MICU1	MICU1	psi-mi:“MI:0407”(direct interaction)	0.560
NRAS	RGL2	psi-mi:“MI:0914”(association)	0.550

BioGRID (118): MICU1 (Affinity Capture-MS), MICU1 (Affinity Capture-MS), MICU1 (Affinity Capture-MS), MICU1 (Affinity Capture-MS), MICU1 (Affinity Capture-MS), MICU1 (Affinity Capture-MS), MICU1 (Affinity Capture-MS), MICU3 (Affinity Capture-MS), MICU1 (Affinity Capture-MS), MICU1 (Affinity Capture-MS), MICU1 (Affinity Capture-MS), GPN3 (Affinity Capture-MS), MICU1 (Affinity Capture-MS), MICU1 (Affinity Capture-MS), MICU1 (Affinity Capture-MS)

ESM2 similar proteins: A0PJX0, A1L1L6, A4IG32, B1A8Z2, B1H2N3, C7A278, D2HZB0, O88456, P04632, P06813, P07090, P22676, P47728, Q08331, Q0IIL1, Q17QE5, Q1RMX9, Q2HJF8, Q2KI69, Q32L26, Q32LU1, Q3T0E8, Q3ZBY3, Q4R518, Q5PPL2, Q5RDF9, Q5ZM73, Q6NVC5, Q6P6Q9, Q6P8Y1, Q6PHZ8, Q6PIL6, Q8BG51, Q8HYN7, Q8IXI2, Q8R426, Q8VCX5, Q8WWF8, Q99828, Q99MG9

Diamond homologs: A2VEI2, A4IG32, A8WQT4, B1H2N3, D2HZB0, Q0IIL1, Q4R518, Q6P6Q9, Q8VCX5, Q95PZ2, Q9BPX6, F1LX07, O75746, Q5RBC8, Q8BH59, Q8CD10, Q8IYU8, Q99P63, Q9SZ45

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
MICU1	“form complex”	MCU_MICUB_variant	binding
MICU1	“form complex”	MCU_MICU1_variant	binding
MICU1	“form complex”	MCU_MICU3_variant	binding
MICU1	“form complex”	MCU_MICU2_variant	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 97 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
Processing of SMDT1	5	51.2×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	12
Uncertain significance	118
Likely benign	151
Benign	34

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
101045	NM_001195518.2(MICU1):c.1072-1G>C	Pathogenic
1033066	NM_001195518.2(MICU1):c.310del (p.Ser104fs)	Pathogenic
1070383	NC_000010.10:g.(?74234858)(74237337_?)del	Pathogenic
1174136	NM_001195518.2(MICU1):c.52C>T (p.Arg18Ter)	Pathogenic
1174137	NG_033179.1:g.(5183_64397)_(64560_68128)_del	Pathogenic
1415240	NM_001195518.2(MICU1):c.598G>T (p.Glu200Ter)	Pathogenic
1444127	NC_000010.10:g.(?74293484)(74311119_?)del	Pathogenic
1453121	NM_001195518.2(MICU1):c.538-1133_538-1130del	Pathogenic
1454356	NM_001195518.2(MICU1):c.459del (p.Arg154fs)	Pathogenic
1459910	NM_001195518.2(MICU1):c.403_407dup (p.Ile137fs)	Pathogenic
1699954	NM_001195518.2:g.(?74326370)(74326571_?)del	Pathogenic
1701868	NM_001195518.2(MICU1):c.385C>T (p.Arg129Ter)	Pathogenic
1946040	NM_001195518.2(MICU1):c.91C>T (p.Arg31Ter)	Pathogenic
1999537	NM_001195518.2(MICU1):c.900del (p.Gln300fs)	Pathogenic
2002061	NM_001195518.2(MICU1):c.439_440del (p.Met147fs)	Pathogenic
2034476	NM_001195518.2(MICU1):c.734del (p.Gln245fs)	Pathogenic
2127778	NM_001195518.2(MICU1):c.263del (p.Lys88fs)	Pathogenic
2425504	NC_000010.10:g.(?74322633)(74322841_?)del	Pathogenic
2425505	NC_000010.10:g.(?74167667)(74183149_?)del	Pathogenic
2425506	NC_000010.10:g.(?74182972)(74326551_?)del	Pathogenic
280156	NM_001195518.2(MICU1):c.638_639del (p.Thr213fs)	Pathogenic
2809049	NM_001195518.2(MICU1):c.931G>T (p.Glu311Ter)	Pathogenic
2874670	NM_001195518.2(MICU1):c.337G>T (p.Glu113Ter)	Pathogenic
2994820	NM_001195518.2(MICU1):c.973_974del (p.Arg325fs)	Pathogenic
3244972	NC_000010.10:g.(?74326371)(74326551_?)del	Pathogenic
3244973	NC_000010.10:g.(?74267893)(74268047_?)del	Pathogenic
3669876	NM_001195518.2(MICU1):c.538-1132dup	Pathogenic
373030	NM_001195518.2(MICU1):c.1072-1G>A	Pathogenic
431145	NM_001195518.2(MICU1):c.1042C>T (p.Gln348Ter)	Pathogenic
431921	NM_001195518.2(MICU1):c.355C>T (p.Arg119Ter)	Pathogenic

SpliceAI

3094 predictions. Top by Δscore:

Variant	Effect	Δscore
10:72368352:TTGCC:T	acceptor_loss	1.0000
10:72368353:TGC:T	acceptor_gain	1.0000
10:72368354:GCC:G	acceptor_loss	1.0000
10:72368356:C:CC	acceptor_gain	1.0000
10:72368356:CT:C	acceptor_loss	1.0000
10:72375868:GGTCA:G	acceptor_gain	1.0000
10:72375869:GTCA:G	acceptor_gain	1.0000
10:72375870:TCA:T	acceptor_gain	1.0000
10:72375871:CA:C	acceptor_gain	1.0000
10:72375871:CAC:C	acceptor_gain	1.0000
10:72375873:C:CC	acceptor_gain	1.0000
10:72375873:C:CG	acceptor_loss	1.0000
10:72375874:T:C	acceptor_loss	1.0000
10:72379479:T:TA	donor_gain	1.0000
10:72407927:A:AG	donor_loss	1.0000
10:72407928:C:CA	donor_loss	1.0000
10:72408035:ACCCT:A	acceptor_loss	1.0000
10:72408036:CC:C	acceptor_gain	1.0000
10:72408037:CC:C	acceptor_gain	1.0000
10:72408037:CCTGC:C	acceptor_loss	1.0000
10:72408038:C:CC	acceptor_gain	1.0000
10:72408038:C:T	acceptor_loss	1.0000
10:72408039:T:A	acceptor_loss	1.0000
10:72423367:TCAAA:T	acceptor_gain	1.0000
10:72423368:CAAA:C	acceptor_gain	1.0000
10:72423368:CAAAC:C	acceptor_gain	1.0000
10:72423372:C:CC	acceptor_gain	1.0000
10:72428061:AAGAG:A	donor_gain	1.0000
10:72475095:CCTA:C	donor_loss	1.0000
10:72475096:CTA:C	donor_loss	1.0000

AlphaMissense

3177 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:72368343:A:G	L428P	1.000
10:72375854:G:T	A400D	1.000
10:72375855:C:G	A400P	1.000
10:72407970:G:T	A380E	1.000
10:72407971:C:G	A380P	1.000
10:72407997:A:G	L371P	1.000
10:72423313:A:G	L331P	1.000
10:72475110:A:G	L308P	1.000
10:72475125:A:G	L303P	1.000
10:72475136:A:C	F299L	1.000
10:72475136:A:T	F299L	1.000
10:72475137:A:G	F299S	1.000
10:72475138:A:G	F299L	1.000
10:72475145:G:C	F296L	1.000
10:72475145:G:T	F296L	1.000
10:72475146:A:G	F296S	1.000
10:72475147:A:G	F296L	1.000
10:72475161:A:G	L291P	1.000
10:72475184:A:C	F283L	1.000
10:72475184:A:T	F283L	1.000
10:72475186:A:G	F283L	1.000
10:72477217:T:G	D231A	1.000
10:72477219:A:C	F230L	1.000
10:72477219:A:T	F230L	1.000
10:72477221:A:G	F230L	1.000
10:72477228:G:C	F227L	1.000
10:72477228:G:T	F227L	1.000
10:72477229:A:G	F227S	1.000
10:72477230:A:G	F227L	1.000
10:72477232:G:T	A226D	1.000

dbSNP variants (sampled 300 via entrez): RS1000008644 (10:72377524 A>C), RS1000011983 (10:72404213 C>T), RS1000043709 (10:72396941 A>G), RS1000073576 (10:72602024 T>C), RS1000076078 (10:72411464 A>G), RS1000080739 (10:72595549 T>C), RS1000086704 (10:72504923 G>A), RS1000095206 (10:72562587 A>C), RS1000095587 (10:72469659 C>A,T), RS1000097304 (10:72458778 C>A,T), RS1000109114 (10:72515895 A>G), RS1000116220 (10:72429775 T>C), RS1000134187 (10:72556404 A>C,G), RS1000134590 (10:72595216 C>G), RS1000140305 (10:72603211 A>G)

Disease associations

OMIM: gene MIM:605084 | disease phenotypes: MIM:615673

GenCC curated gene-disease

Disease	Classification	Inheritance
proximal myopathy with extrapyramidal signs	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (3): proximal myopathy with extrapyramidal signs (MONDO:0014300), neurodevelopmental disorder (MONDO:0700092), congenital nervous system disorder (MONDO:0002320)

Orphanet (1): Proximal myopathy with extrapyramidal signs (Orphanet:401768)

HPO phenotypes

67 total (30 of 67 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000275	Narrow face
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000365	Hearing impairment
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000508	Ptosis
HP:0000602	Ophthalmoplegia
HP:0000646	Amblyopia
HP:0000648	Optic atrophy
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000831	Insulin-resistant diabetes mellitus
HP:0001027	Soft, doughy skin
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001270	Motor delay
HP:0001288	Gait disturbance
HP:0001328	Specific learning disability
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001382	Joint hypermobility
HP:0001510	Growth delay
HP:0001629	Ventricular septal defect
HP:0001638	Cardiomyopathy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_290	Refractive error	2.000000e-17

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other ic — Mitochondrial calcium uniporter (MCU) complex

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	5
sodium arsenite	affects expression, decreases expression, increases abundance, increases expression	3
Valproic Acid	affects expression, increases expression	3
Aflatoxin B1	decreases expression, decreases methylation	2
Cadmium Chloride	increases expression	2
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
uranyl acetate	affects expression	1
bisphenol A	increases expression	1
arsenite	affects binding, increases reaction	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
ICG 001	decreases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arsenic	decreases expression, increases abundance	1
Cisplatin	decreases expression	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Ketoconazole	increases expression	1
Methapyrilene	decreases methylation	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Silicon Dioxide	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tretinoin	increases expression	1
Uranium	affects expression	1
Antirheumatic Agents	increases expression	1
Lactic Acid	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0I1	Ubigene HeLa MICU1 KO	Cancer cell line	Female
CVCL_E2C9	HAP1 MICU1 (-) 1	Cancer cell line	Male
CVCL_E2CA	HAP1 MICU1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice