COA3

Summary

COA3 (cytochrome c oxidase assembly factor 3, HGNC:24990) is a protein-coding gene on chromosome 17q21.2, encoding Cytochrome c oxidase assembly factor 3 homolog, mitochondrial (Q9Y2R0). Core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly. It is a selective cancer dependency (DepMap: 17.7% of cell lines).

This gene encodes a member of the cytochrome c oxidase assembly factor family. Studies of a related gene in fly suggest that the encoded protein is localized to mitochondria and is essential for cytochrome c oxidase function.

Source: NCBI Gene 28958 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cytochrome-c oxidase deficiency disease (Supportive, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 46 total
• Phenotypes (HPO): 11
• Cancer dependency (DepMap): dependent in 17.7% of screened cell lines
• MANE Select transcript: NM_001040431

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24990
Approved symbol	COA3
Name	cytochrome c oxidase assembly factor 3
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	HSPC009, MITRAC12, COX25, hCOA3
Ensembl gene	ENSG00000183978
Ensembl biotype	protein_coding
OMIM	614775
Entrez	28958

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 nonsense_mediated_decay

ENST00000328434, ENST00000586680

RefSeq mRNA: 1 — MANE Select: NM_001040431 NM_001040431

CCDS: CCDS32660

Canonical transcript exons

ENST00000328434 — 2 exons

Exon	Start	End
ENSE00001318691	42797625	42798167
ENSE00002974911	42798468	42798704

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 98.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.2827 / max 169.3150, expressed in 1809 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
166188	31.2827	1809

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	98.95	gold quality
corpus epididymis	UBERON:0004359	98.72	gold quality
renal medulla	UBERON:0000362	98.26	gold quality
body of pancreas	UBERON:0001150	98.26	gold quality
metanephros cortex	UBERON:0010533	98.07	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.81	gold quality
colonic mucosa	UBERON:0000317	97.80	gold quality
oral cavity	UBERON:0000167	97.75	gold quality
duodenum	UBERON:0002114	97.55	gold quality
body of stomach	UBERON:0001161	97.53	gold quality
gingiva	UBERON:0001828	97.52	gold quality
gingival epithelium	UBERON:0001949	97.45	gold quality
cervix squamous epithelium	UBERON:0006922	97.42	gold quality
adult organism	UBERON:0007023	97.37	gold quality
bronchial epithelial cell	CL:0002328	97.36	gold quality
transverse colon	UBERON:0001157	97.35	gold quality
prefrontal cortex	UBERON:0000451	97.31	gold quality
anterior cingulate cortex	UBERON:0009835	97.29	gold quality
adult mammalian kidney	UBERON:0000082	97.28	gold quality
cingulate cortex	UBERON:0003027	97.26	gold quality
rectum	UBERON:0001052	97.23	gold quality
right frontal lobe	UBERON:0002810	97.23	gold quality
tongue squamous epithelium	UBERON:0006919	97.23	gold quality
epithelium of bronchus	UBERON:0002031	97.21	gold quality
esophagus mucosa	UBERON:0002469	97.15	gold quality
amygdala	UBERON:0001876	97.14	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.14	gold quality
cortex of kidney	UBERON:0001225	97.11	gold quality
nephron tubule	UBERON:0001231	97.09	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.09	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	27.01
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 17.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 6)

• Human ortholog of fungal COA3 (Cytochrome oxidase assembly) (PMID:22356826)
• Study comprehensively identified mammalian cytochrome c oxidase assembly factors. These analyses led to the discoveryof MITRAC12, which defines the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase)complexes. (PMID:23260140)
• hCOA3 stabilizes COX1 co-translationally and promotes its assembly with COX partner subunits. (PMID:23362268)
• COX14 was undetectable in COA3 subject fibroblasts, and that COA3 was undetectable in fibroblasts from a COX14 subject, demonstrating the interdependence of these two COX assembly factors (PMID:25604084)
• Data show that mitochondrial protein ccdc56/MITRAC12/COA3 positively regulates mitochondrial fission by recruiting the fission factor Drp1. (PMID:26358295)
• Data suggest that COX assembly factor 3 (hCOA3) is a disordered protein and that the flexibility of hCOA3 is crucial for its interaction with other proteins to favor mitochondrial protein translocation and assembly of proteins involved in the respiratory chain. (PMID:27791355)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	coa3a	ENSDARG00000100585
mus_musculus	Coa3	ENSMUSG00000017188
rattus_norvegicus	Coa3	ENSRNOG00000020487
caenorhabditis_elegans		WBGENE00018046

Protein

Protein identifiers

Cytochrome c oxidase assembly factor 3 homolog, mitochondrial — Q9Y2R0 (reviewed: Q9Y2R0)

Alternative names: Coiled-coil domain-containing protein 56, Mitochondrial translation regulation assembly intermediate of cytochrome c oxidase protein of 12 kDa

All UniProt accessions (2): Q9Y2R0, K7EPV0

UniProt curated annotations — full annotation on UniProt →

Function. Core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly. MITRAC complexes regulate both translation of mitochondrial encoded components and assembly of nuclear-encoded components imported in mitochondrion. Required for efficient translation of MT-CO1 and mitochondrial respiratory chain complex IV assembly.

Subunit / interactions. Along with COX14, core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex. Interacts with MT-CO1/COX1, SMIM20, SURF1 and TIMM21.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Mitochondrial complex IV deficiency, nuclear type 14 (MC4DN14) [MIM:619058] An autosomal recessive mitochondrial disorder with onset in early childhood. MC4DN14 is characterized by developmental delay, cognitive impairment, motor delay, abnormal gait, sensorimotor demyelinating polyneuropathy, exercise intolerance, obesity, and short stature. Serum lactate levels are marginally increased. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the COA3 family.

RefSeq proteins (1): NP_001035521* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018628	Coa3_CC	Domain
IPR041752	Coa3	Family

Pfam: PF09813

UniProt features (9 total): topological domain 2, initiator methionine 1, chain 1, transmembrane region 1, region of interest 1, coiled-coil region 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2R0-F1	77.32	0.25

Functional residue map

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

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9864848	Complex IV assembly

MSigDB gene sets: 181 (showing top): GOBP_RESPIRATORY_CHAIN_COMPLEX_IV_ASSEMBLY, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_MITOCHONDRIAL_TRANSLATION, RACCACAR_AML_Q6, CAGCTG_AP4_Q5, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_PROTEIN_MATURATION, RGTTAMWNATT_HNF1_01, GOCC_MITOCHONDRIAL_ENVELOPE, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_13, TGANTCA_AP1_C, GOBP_PROTEIN_FOLDING

GO Biological Process (2): mitochondrial respiratory chain complex IV assembly (GO:0033617), positive regulation of mitochondrial translation (GO:0070131)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	2
respiratory chain complex IV assembly	1
mitochondrial respiratory chain complex assembly	1
mitochondrial translation	1
positive regulation of translation	1
regulation of mitochondrial translation	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
cellular anatomical structure	1
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

1104 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COA3	COX14	Q96I36	984
COA3	SURF1	Q15526	877
COA3	COA6	Q5JTJ3	807
COA3	COX15	Q7KZN9	797
COA3	COA1	Q9GZY4	774
COA3	COX16	Q9P0S2	746
COA3	TACO1	Q9BSH4	722
COA3	MSS51	Q4VC12	716
COA3	SMIM20	Q8N5G0	703
COA3	COX5A	P20674	695
COA3	COX10	Q12887	683
COA3	COX20	Q5RI15	642
COA3	CMC1	Q7Z7K0	618
COA3	COA5	Q86WW8	612
COA3	COX5B	P10606	604

IntAct

47 interactions, top by confidence:

A	B	Type	Score
COA3	MT-CO1	psi-mi:“MI:0914”(association)	0.610
MT-CO1	COA3	psi-mi:“MI:0915”(physical association)	0.610
COA3	MT-CO1	psi-mi:“MI:0915”(physical association)	0.610
SURF1	COA3	psi-mi:“MI:0915”(physical association)	0.560
TIMM21	TIMM23	psi-mi:“MI:0914”(association)	0.500
COA3	ATAD3A	psi-mi:“MI:0915”(physical association)	0.460
COA3	ATAD3A	psi-mi:“MI:0403”(colocalization)	0.460
Smc3	PDS5B	psi-mi:“MI:0914”(association)	0.350
K8.1	EXOC5	psi-mi:“MI:0914”(association)	0.350
MAD2L2		psi-mi:“MI:0914”(association)	0.350
DND1	RPSA2	psi-mi:“MI:0914”(association)	0.350
NMES1	NDUFS8	psi-mi:“MI:0914”(association)	0.350
COQ9	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFA4	NUDT19	psi-mi:“MI:0914”(association)	0.350
CHCHD10	RNASEH1	psi-mi:“MI:0914”(association)	0.350
NDUFA4	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NMES1	COX7A2L	psi-mi:“MI:0914”(association)	0.350
COQ9	ACOT7	psi-mi:“MI:0914”(association)	0.350

BioGRID (111): COA3 (Affinity Capture-RNA), COA3 (Affinity Capture-MS), COA3 (Affinity Capture-MS), COA3 (Affinity Capture-MS), COA3 (Affinity Capture-MS), COA3 (Affinity Capture-MS), COX1 (Affinity Capture-Western), COX2 (Affinity Capture-Western), COX3 (Affinity Capture-Western), COX4I1 (Affinity Capture-Western), COX4I2 (Affinity Capture-Western), COX5A (Affinity Capture-Western), NDUFA9 (Affinity Capture-Western), NDUFV1 (Affinity Capture-Western), TUFM (Affinity Capture-Western)

ESM2 similar proteins: A0A1N7SYS3, A1C8Z3, A1CMM2, A1XQS1, A3LQD9, A5DM93, A5DTG8, A6R620, A6ZUI6, A7TFK6, B3DFP2, B3LI56, C5DE77, C5E368, C6Y4C1, C7GT24, C8Z970, P0CM84, P0CM85, P37267, P38958, P47081, Q02771, Q0UIR3, Q1DME3, Q2PIY2, Q3T0E3, Q4I8P5, Q52ZA1, Q59QC6, Q5ACH7, Q5AXJ9, Q5R7J0, Q6BI17, Q6BY05, Q6C5S0, Q6CCF6, Q6CHT7, Q6CJX5, Q6CK73

Diamond homologs: A8KB87, P0DKM0, Q3T0E3, Q5R7J0, Q9D2R6, Q9Y2R0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
COA3	“form complex”	“MITRAC complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 40 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
Complex IV assembly	10	81.6×	7e-16
Cytoprotection by HMOX1	5	32.9×	7e-06
Respiratory electron transport	9	30.6×	2e-10
TP53 Regulates Metabolic Genes	5	23.2×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, cytochrome c to oxygen	5	112.7×	1e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	9
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

975 predictions. Top by Δscore:

Variant	Effect	Δscore
17:42796319:CCTG:C	donor_loss	1.0000
17:42796321:TGGTG:T	donor_loss	1.0000
17:42796323:G:GC	donor_loss	1.0000
17:42796324:T:G	donor_loss	1.0000
17:42796546:G:GT	donor_gain	1.0000
17:42796574:GGATG:G	donor_gain	1.0000
17:42796575:G:GT	donor_gain	1.0000
17:42796684:A:AG	acceptor_gain	1.0000
17:42796685:G:GG	acceptor_gain	1.0000
17:42795679:C:G	donor_gain	0.9900
17:42795804:G:GT	donor_gain	0.9900
17:42795804:G:T	donor_gain	0.9900
17:42796031:GAA:G	donor_gain	0.9900
17:42796034:G:GG	donor_gain	0.9900
17:42796323:G:GG	donor_gain	0.9900
17:42796325:GA:G	donor_loss	0.9900
17:42796564:G:GT	donor_gain	0.9900
17:42796564:G:T	donor_gain	0.9900
17:42796576:A:T	donor_gain	0.9900
17:42796684:AGT:A	acceptor_gain	0.9900
17:42796685:GT:G	acceptor_gain	0.9900
17:42796685:GTG:G	acceptor_gain	0.9900
17:42796685:GTGA:G	acceptor_gain	0.9900
17:42798497:AGG:A	donor_gain	0.9900
17:42795678:GC:G	donor_gain	0.9800
17:42795832:C:G	donor_gain	0.9800
17:42796117:CCTCA:C	acceptor_loss	0.9800
17:42796119:TCAG:T	acceptor_loss	0.9800
17:42796120:CA:C	acceptor_loss	0.9800
17:42796121:A:AG	acceptor_gain	0.9800

AlphaMissense

652 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:42798488:C:T	G65E	0.985
17:42798164:C:T	G73D	0.981
17:42798485:G:T	A66D	0.977
17:42798165:C:G	G73R	0.975
17:42798489:C:G	G65R	0.972
17:42798489:C:T	G65R	0.972
17:42798500:C:T	G61D	0.972
17:42798495:C:G	G63R	0.969
17:42798130:G:C	F84L	0.968
17:42798130:G:T	F84L	0.968
17:42798132:A:G	F84L	0.968
17:42798501:C:G	G61R	0.963
17:42798473:G:T	A70D	0.961
17:42798494:C:T	G63D	0.956
17:42798131:A:G	F84S	0.955
17:42798479:A:T	V68E	0.947
17:42798482:A:C	L67R	0.946
17:42798131:A:C	F84C	0.940
17:42798139:C:A	Q81H	0.931
17:42798139:C:G	Q81H	0.931
17:42798491:A:T	I64N	0.931
17:42798511:G:C	N57K	0.931
17:42798511:G:T	N57K	0.931
17:42798150:A:G	S78P	0.920
17:42798497:A:C	L62R	0.920
17:42798158:G:A	T75I	0.919
17:42798137:T:A	E82V	0.917
17:42798144:A:G	S80P	0.916
17:42798162:A:C	Y74D	0.912
17:42798470:A:T	I71N	0.906

dbSNP variants (sampled 300 via entrez): RS1000388767 (17:42800324 T>C), RS1000665020 (17:42799680 A>T), RS1001127334 (17:42798636 C>G,T), RS1002953265 (17:42797281 C>A,T), RS1003290125 (17:42797648 T>C), RS1006232860 (17:42797533 T>A), RS1006870933 (17:42800541 T>C), RS1010897209 (17:42800356 G>A), RS1012987656 (17:42798229 C>A), RS1013013292 (17:42797716 C>T), RS1013041045 (17:42798593 A>C), RS1013044914 (17:42797303 A>G), RS1013891505 (17:42800287 C>T), RS1014185046 (17:42800611 G>A,T), RS1014963918 (17:42797919 T>C)

Disease associations

OMIM: gene MIM:614775 | disease phenotypes: MIM:619058, MIM:220110

GenCC curated gene-disease

Disease	Classification	Inheritance
cytochrome-c oxidase deficiency disease	Supportive	Autosomal recessive
mitochondrial complex IV deficiency, nuclear type 14	Limited	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Limited	AR

Mondo (3): mitochondrial complex IV deficiency, nuclear type 14 (MONDO:0033649), mitochondrial complex IV deficiency, nuclear type 1 (MONDO:0700250), (MONDO:0009068)

Orphanet (0):

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000286	Epicanthus
HP:0000490	Deeply set eye
HP:0001263	Global developmental delay
HP:0001513	Obesity
HP:0003546	Exercise intolerance
HP:0003688	Cytochrome C oxidase-negative muscle fibers
HP:0004322	Short stature
HP:0007141	Sensorimotor neuropathy
HP:0008347	Decreased activity of mitochondrial complex IV
HP:0100543	Cognitive impairment

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression, decreases reaction, increases abundance	2
sodium arsenite	decreases expression, increases expression	2
cobaltous chloride	decreases expression	2
Acetaminophen	decreases expression	2
Valproic Acid	affects cotreatment, increases expression, affects expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
ginger extract	decreases reaction, increases abundance, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
corosolic acid	decreases expression	1
ICG 001	increases expression	1
Benzo(a)pyrene	decreases expression	1
Cadmium	increases abundance, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Oils, Volatile	decreases reaction, increases abundance, increases expression	1
Thiram	decreases expression	1
Urethane	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Cyclosporine	decreases expression	1
Cadmium Chloride	increases abundance, increases expression	1
Okadaic Acid	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2UR	Abcam HEK293T COA3 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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