UQCC3

Summary

UQCC3 (ubiquinol-cytochrome c reductase complex assembly factor 3, HGNC:34399) is a protein-coding gene on chromosome 11q12.3, encoding Ubiquinol-cytochrome-c reductase complex assembly factor 3 (Q6UW78). Required for the assembly of the ubiquinol-cytochrome c reductase complex (mitochondrial respiratory chain complex III or cytochrome b-c1 complex), mediating cytochrome b recruitment and probably stabilization within the complex. It is a selective cancer dependency (DepMap: 10.7% of cell lines).

Complex III is a mitochondrial inner membrane protein complex that transfers electrons from ubiquinol to cytochrome c. This gene encodes a protein that functions in complex III assembly. Mutations in this gene result in Mitochondrial complex III deficiency, nuclear type 9.

Source: NCBI Gene 790955 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial complex III deficiency nuclear type 9 (Moderate, GenCC) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 4 total
• Phenotypes (HPO): 17
• Cancer dependency (DepMap): dependent in 10.7% of screened cell lines
• MANE Select transcript: NM_001085372

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:34399
Approved symbol	UQCC3
Name	ubiquinol-cytochrome c reductase complex assembly factor 3
Location	11q12.3
Locus type	gene with protein product
Status	Approved
Aliases	UNQ655
Ensembl gene	ENSG00000204922
Ensembl biotype	protein_coding
OMIM	616097
Entrez	790955

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000377953, ENST00000531323, ENST00000889754, ENST00000889755, ENST00000925582

RefSeq mRNA: 1 — MANE Select: NM_001085372 NM_001085372

CCDS: CCDS41658

Canonical transcript exons

ENST00000377953 — 2 exons

Exon	Start	End
ENSE00001475615	62671953	62673686
ENSE00001475616	62671673	62671865

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 91.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.2774 / max 113.3504, expressed in 1770 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114724	14.2774	1770

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	91.84	gold quality
upper arm skin	UBERON:0004263	91.02	silver quality
mucosa of transverse colon	UBERON:0004991	90.32	gold quality
gingival epithelium	UBERON:0001949	86.38	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.72	gold quality
tendon of biceps brachii	UBERON:0008188	85.36	gold quality
palpebral conjunctiva	UBERON:0001812	85.07	gold quality
gingiva	UBERON:0001828	84.88	gold quality
parotid gland	UBERON:0001831	84.84	gold quality
right adrenal gland cortex	UBERON:0035827	84.59	gold quality
right adrenal gland	UBERON:0001233	84.35	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.33	gold quality
pancreatic ductal cell	CL:0002079	84.19	silver quality
left adrenal gland cortex	UBERON:0035825	83.41	gold quality
adrenal cortex	UBERON:0001235	83.26	gold quality
left adrenal gland	UBERON:0001234	83.24	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	82.45	gold quality
gastrocnemius	UBERON:0001388	82.31	gold quality
muscle of leg	UBERON:0001383	82.19	gold quality
lower esophagus mucosa	UBERON:0035834	82.15	gold quality
esophagus mucosa	UBERON:0002469	82.04	gold quality
apex of heart	UBERON:0002098	81.53	gold quality
vastus lateralis	UBERON:0001379	81.38	silver quality
quadriceps femoris	UBERON:0001377	81.34	silver quality
transverse colon	UBERON:0001157	81.32	gold quality
adult mammalian kidney	UBERON:0000082	80.96	gold quality
adrenal gland	UBERON:0002369	80.83	gold quality
nasal cavity mucosa	UBERON:0001826	80.78	gold quality
body of stomach	UBERON:0001161	80.77	gold quality
amniotic fluid	UBERON:0000173	80.75	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.43
E-MTAB-6524	no	266.77

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

60 targeting UQCC3, 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-3613-3P	100.00	76.36	7965
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-885-5P	99.59	68.59	879
HSA-MIR-7106-5P	99.53	67.47	3574

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 6)

• AY358935 is a predicted secretary protein with a small molecular weight that might have important functions in cellular proliferation and anti-viral innate immune regulation. (PMID:20159687)
• UQCC3 functions in complex III assembly and that the c.59T>A mutation has a causal role in complex III deficiency. (PMID:25008109)
• C11orf83 depletion in HeLa cells caused abnormal crista morphology, higher sensitivity to apoptosis, a decreased ATP level due to impaired respiration and subtle, but significant, changes in cardiolipin composition. (PMID:25605331)
• Mitochondrial C11orf83 is a potent antiviral protein independent of interferon production; and knockdown of either OAS3 or RNase L impaired the antiviral capability of C11orf83. (PMID:28418037)
• AY358935 gene has an anti-VSV effect, and its anti-virus mechanism may involve the interferon-associated natural immune response. (PMID:31642232)
• Mitochondrial UQCC3 Modulates Hypoxia Adaptation by Orchestrating OXPHOS and Glycolysis in Hepatocellular Carcinoma. (PMID:33147459)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Uqcc3	ENSMUSG00000071654
rattus_norvegicus		ENSRNOG00000062467
rattus_norvegicus	LOC120093241	ENSRNOG00000062523
rattus_norvegicus	Uqcc3	ENSRNOG00000084496

Protein

Protein identifiers

Ubiquinol-cytochrome-c reductase complex assembly factor 3 — Q6UW78 (reviewed: Q6UW78)

Alternative names: Assembly factor CBP4 homolog

All UniProt accessions (1): Q6UW78

UniProt curated annotations — full annotation on UniProt →

Function. Required for the assembly of the ubiquinol-cytochrome c reductase complex (mitochondrial respiratory chain complex III or cytochrome b-c1 complex), mediating cytochrome b recruitment and probably stabilization within the complex. Thereby, plays an important role in ATP production by mitochondria. Cardiolipin-binding protein, it may also control the cardiolipin composition of mitochondria membranes and their morphology.

Subunit / interactions. Associates with the ubiquinol-cytochrome c reductase complex (mitochondrial respiratory chain complex III or cytochrome b-c1 complex). Interacts with UQCC1. Forms a complex, named COMC, composed of UQCC1, UQCC2; UQCC3 and UQCC4; mediates MT-CYB hemylation and association with the first nuclear-encoded complex III subunit UQCRQ.

Subcellular location. Mitochondrion inner membrane.

Post-translational modifications. Probably cleaved by OMA1 under mitochondrial stress conditions.

Disease relevance. Mitochondrial complex III deficiency, nuclear type 9 (MC3DN9) [MIM:616111] A form of mitochondrial complex III deficiency, a disorder of the mitochondrial respiratory chain resulting in a highly variable phenotype depending on which tissues are affected. MC3DN9 clinical features include feeding difficulties, hypoglycemia, severe lactic acidosis, and delayed psychomotor development. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the UQCC3 family.

RefSeq proteins (1): NP_001078841* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR027896	UQCC3	Family

Pfam: PF15141

UniProt features (8 total): topological domain 2, chain 1, transmembrane region 1, region of interest 1, sequence variant 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UW78-F1	74.18	0.15

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
5–6	loss of localization to the mitochondria.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9865881	Complex III assembly

MSigDB gene sets: 155 (showing top): GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CRISTAE_FORMATION, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_MITOCHONDRIAL_ELECTRON_TRANSPORT_UBIQUINOL_TO_CYTOCHROME_C, GOBP_ATP_BIOSYNTHETIC_PROCESS, GOBP_INNER_MITOCHONDRIAL_MEMBRANE_ORGANIZATION, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS

GO Biological Process (4): mitochondrial electron transport, ubiquinol to cytochrome c (GO:0006122), ATP biosynthetic process (GO:0006754), mitochondrial respiratory chain complex III assembly (GO:0034551), cristae formation (GO:0042407)

GO Molecular Function (2): phosphatidic acid binding (GO:0070300), cardiolipin binding (GO:1901612)

GO Cellular Component (5): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), cytosol (GO:0005829), membrane (GO:0016020)

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
cellular anatomical structure	3
cytoplasm	2
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
purine ribonucleotide biosynthetic process	1
purine ribonucleoside triphosphate biosynthetic process	1
ATP metabolic process	1
mitochondrion	1
respiratory chain complex III assembly	1
mitochondrial respiratory chain complex assembly	1
inner mitochondrial membrane organization	1
phospholipid binding	1
anion binding	1
phosphatidylglycerol binding	1
nuclear lumen	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1

Protein interactions and networks

STRING

698 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UQCC3	LYRM7	Q5U5X0	719
UQCC3	UQCC1	Q9NVA1	705
UQCC3	TTC19	Q6DKK2	689
UQCC3	UQCC2	Q9BRT2	678
UQCC3	BCS1L	Q9Y276	625
UQCC3	UQCRC2	P22695	495
UQCC3	CSTPP1	Q9H6J7	488
UQCC3	UQCRB	P14927	443
UQCC3	DMAC2	Q9NW81	434
UQCC3	CYC1	P08574	432
UQCC3	HIGD1A	Q9Y241	409
UQCC3	HTD2	P86397	403
UQCC3	UQCRQ	O14949	401
UQCC3	COX7A2L	O14548	391
UQCC3	PLAAT5	Q96KN8	383

IntAct

12 interactions, top by confidence:

A	B	Type	Score
UQCRQ	COX7A2L	psi-mi:“MI:0914”(association)	0.640
NCEH1	CLGN	psi-mi:“MI:0914”(association)	0.530
MMP26	NME4	psi-mi:“MI:0914”(association)	0.350
SLC16A11	ESYT2	psi-mi:“MI:0914”(association)	0.350
FFAR1	SLC12A8	psi-mi:“MI:0914”(association)	0.350
RAMP3	MGST3	psi-mi:“MI:0914”(association)	0.350
BORCS6	UQCRQ	psi-mi:“MI:0914”(association)	0.350
GGH	CLGN	psi-mi:“MI:0914”(association)	0.350
SCYL3	CHEK1	psi-mi:“MI:0914”(association)	0.350
TMEM169	PTGES3L-AARSD1	psi-mi:“MI:0914”(association)	0.350
PHLDA3	UQCC3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (21): UQCC3 (Affinity Capture-MS), UQCC3 (Affinity Capture-MS), UQCC3 (Affinity Capture-MS), UQCC3 (Proximity Label-MS), UQCC3 (Proximity Label-MS), UQCC3 (Proximity Label-MS), UQCC3 (Affinity Capture-MS), UQCC3 (Affinity Capture-MS), UQCC3 (Affinity Capture-MS), UQCC3 (Affinity Capture-MS), UQCC3 (Affinity Capture-MS), UQCC3 (Affinity Capture-MS), UQCC3 (Affinity Capture-MS), UQCC3 (Affinity Capture-MS), UQCC3 (Affinity Capture-MS)

ESM2 similar proteins: A1CMM2, A1DLB6, A2R065, A3LQD9, A4RC22, A5DM93, A5DTG8, A6R620, A6SAY2, A6ZUI6, A7EJE5, A7TFK6, A8PYF7, B3DFP2, B3LI56, C4R127, C5E1G5, C5E368, C6Y4C1, C6Y4C7, C7GT24, C8Z970, G2TRJ9, P0CD94, P37267, Q02771, Q0CGN5, Q0ULB7, Q1DHX9, Q2H4Y0, Q2KP58, Q2UE23, Q3E823, Q55GW4, Q59QC6, Q5ASG4, Q6BI17, Q6BL60, Q6C5S0, Q6CJX5

Diamond homologs: B3DFP2, P0CD94, Q148G8, Q2KP58, Q6UW78, Q8K2T4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

659 predictions. Top by Δscore:

Variant	Effect	Δscore
11:62671547:AACCC:A	donor_gain	1.0000
11:62671515:AGC:A	donor_gain	0.9900
11:62671545:TCA:T	donor_gain	0.9900
11:62671551:C:CA	donor_gain	0.9900
11:62671596:T:TA	donor_gain	0.9900
11:62671629:T:C	donor_gain	0.9900
11:62671534:T:TA	donor_gain	0.9800
11:62671537:TGGAC:T	donor_gain	0.9700
11:62671562:A:C	donor_gain	0.9700
11:62671854:G:GT	donor_gain	0.9700
11:62671557:G:C	donor_gain	0.9600
11:62671579:T:A	donor_gain	0.9600
11:62671593:G:C	donor_gain	0.9600
11:62671608:T:TA	donor_gain	0.9600
11:62671407:C:CT	acceptor_gain	0.9500
11:62671515:AG:A	donor_gain	0.9500
11:62671558:CTAAA:C	donor_loss	0.9500
11:62671560:AAAC:A	donor_loss	0.9500
11:62671562:A:AT	donor_loss	0.9500
11:62671563:C:CT	donor_loss	0.9500
11:62671564:C:A	donor_loss	0.9500
11:62671847:G:GT	donor_gain	0.9400
11:62671861:TAAAG:T	donor_loss	0.9300
11:62671862:AAAGG:A	donor_loss	0.9300
11:62671863:AAG:A	donor_loss	0.9300
11:62671864:AG:A	donor_loss	0.9300
11:62671865:G:GC	donor_loss	0.9300
11:62671867:T:A	donor_loss	0.9300
11:62671952:GGA:G	acceptor_gain	0.9300
11:62671516:G:C	donor_gain	0.9200

AlphaMissense

589 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:62671807:G:A	G21D	0.979
11:62672031:G:C	A67P	0.979
11:62671806:G:C	G21R	0.976
11:62672051:C:A	N73K	0.971
11:62672051:C:G	N73K	0.971
11:62671801:G:A	G19D	0.962
11:62671800:G:C	G19R	0.960
11:62671788:G:C	G15R	0.957
11:62672050:A:T	N73I	0.949
11:62671794:G:A	G17R	0.945
11:62671794:G:C	G17R	0.945
11:62671789:G:A	G15D	0.943
11:62672034:G:C	A68P	0.940
11:62671798:C:A	A18D	0.938
11:62672050:A:G	N73S	0.928
11:62672049:A:C	N73H	0.927
11:62672063:G:C	R77S	0.926
11:62672063:G:T	R77S	0.926
11:62671816:T:G	L24R	0.925
11:62671816:T:A	L24H	0.922
11:62672049:A:G	N73D	0.922
11:62672050:A:C	N73T	0.919
11:62672049:A:T	N73Y	0.914
11:62672023:T:C	L64P	0.908
11:62671813:C:A	A23E	0.906
11:62671795:G:A	G17E	0.905
11:62671777:T:A	V11D	0.904
11:62671780:C:A	A12E	0.902
11:62672062:G:C	R77T	0.898
11:62672008:T:C	L59P	0.897

dbSNP variants (sampled 300 via entrez): RS1001545821 (11:62672222 C>T), RS1002205940 (11:62672661 G>C), RS1002570642 (11:62672533 G>A,C,T), RS1002810598 (11:62673958 G>A), RS1002952502 (11:62671097 C>G), RS1003158617 (11:62671327 C>G,T), RS1003167972 (11:62674163 G>A), RS1003908696 (11:62671599 T>C,G), RS1003960851 (11:62671503 G>A), RS1004444868 (11:62673284 A>G), RS1004916021 (11:62672975 A>G), RS1004968356 (11:62672727 T>C), RS1005410748 (11:62672191 C>A,T), RS1005965666 (11:62673987 C>G), RS1006418495 (11:62671061 T>C,G)

Disease associations

OMIM: gene MIM:616097 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex III deficiency nuclear type 9	Moderate	Autosomal recessive
mitochondrial complex III deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Limited	AR

Mondo (2): mitochondrial complex III deficiency (MONDO:0015448), mitochondrial complex III deficiency nuclear type 9 (MONDO:0014496)

Orphanet (0):

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000540	Hypermetropia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001324	Muscle weakness
HP:0001943	Hypoglycemia
HP:0002151	Increased circulating lactate concentration
HP:0002360	Sleep disturbance
HP:0002490	Increased CSF lactate
HP:0003128	Lactic acidosis
HP:0003623	Neonatal onset
HP:0004900	Severe lactic acidosis
HP:0007109	Periventricular cysts
HP:0008897	Postnatal growth retardation
HP:0011924	Decreased activity of mitochondrial complex III
HP:0011968	Feeding difficulties
HP:0032653	Elevated lactate:pyruvate ratio

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005956_12	Waist-to-hip ratio adjusted for BMI	2.000000e-06
GCST005956_2	Waist-to-hip ratio adjusted for BMI	1.000000e-08
GCST005962_37	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	5.000000e-07
GCST005962_51	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression	2
Cadmium Chloride	decreases expression	2
beta-lapachone	increases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
K 7174	decreases expression	1
ICG 001	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	increases expression, affects cotreatment, decreases reaction	1
Sunitinib	decreases expression	1
Ethanol	affects cotreatment, decreases reaction, increases expression	1
Benzo(a)pyrene	affects cotreatment, decreases reaction, increases expression	1
Coumestrol	increases expression	1
Naled	affects expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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