COX4I1

Summary

COX4I1 (cytochrome c oxidase subunit 4I1, HGNC:2265) is a protein-coding gene on chromosome 16q24.1, encoding Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (P13073). Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. It is a selective cancer dependency (DepMap: 23.8% of cell lines).

Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane. The complex consists of 13 mitochondrial- and nuclear-encoded subunits. The mitochondrially-encoded subunits perform the electron transfer and proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex. This gene encodes the nuclear-encoded subunit IV isoform 1 of the human mitochondrial respiratory chain enzyme. It is located at the 3’ of the NOC4 (neighbor of COX4) gene in a head-to-head orientation, and shares a promoter with it. Pseudogenes related to this gene are located on chromosomes 13 and 14. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 1327 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cytochrome-c oxidase deficiency disease (Supportive, GenCC) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 51 total — 2 pathogenic
• Phenotypes (HPO): 26
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 23.8% of screened cell lines
• MANE Select transcript: NM_001861

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2265
Approved symbol	COX4I1
Name	cytochrome c oxidase subunit 4I1
Location	16q24.1
Locus type	gene with protein product
Status	Approved
Aliases	COX4-1, COXIV, COXIV-1
Ensembl gene	ENSG00000131143
Ensembl biotype	protein_coding
OMIM	123864
Entrez	1327

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 23 protein_coding, 7 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000253452, ENST00000561569, ENST00000562336, ENST00000562929, ENST00000563774, ENST00000564544, ENST00000564648, ENST00000564903, ENST00000565078, ENST00000566115, ENST00000566405, ENST00000566617, ENST00000567241, ENST00000567266, ENST00000568339, ENST00000568794, ENST00000569997, ENST00000570123, ENST00000906734, ENST00000906735, ENST00000906736, ENST00000906737, ENST00000906738, ENST00000906739, ENST00000924846, ENST00000924847, ENST00000924848, ENST00000924849, ENST00000924850, ENST00000924851, ENST00000924852, ENST00000924853, ENST00000968294, ENST00000968295

RefSeq mRNA: 6 — MANE Select: NM_001861 NM_001318786, NM_001318788, NM_001318794, NM_001318797, NM_001318802, NM_001861

CCDS: CCDS10955, CCDS82020

Canonical transcript exons

ENST00000253452 — 5 exons

Exon	Start	End
ENSE00001104549	85799695	85799752
ENSE00001176352	85804937	85805104
ENSE00003459323	85805733	85805864
ENSE00003529343	85801205	85801278
ENSE00003893824	85806738	85807068

Expression profiles

Bgee: expression breadth ubiquitous, 306 present calls, max score 99.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 296.1624 / max 1199.5657, expressed in 1828 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155420	239.6098	1828
155421	25.7499	1818
155419	15.8704	1809
155418	14.8049	1811
155416	0.0763	21
155417	0.0419	19
207992	0.0093	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.88	gold quality
heart left ventricle	UBERON:0002084	99.82	gold quality
cardiac ventricle	UBERON:0002082	99.81	gold quality
right atrium auricular region	UBERON:0006631	99.80	gold quality
prefrontal cortex	UBERON:0000451	99.79	gold quality
heart right ventricle	UBERON:0002080	99.79	gold quality
cardiac atrium	UBERON:0002081	99.79	gold quality
middle temporal gyrus	UBERON:0002771	99.77	gold quality
left ventricle myocardium	UBERON:0006566	99.77	gold quality
right frontal lobe	UBERON:0002810	99.76	gold quality
myocardium	UBERON:0002349	99.75	gold quality
cervix squamous epithelium	UBERON:0006922	99.75	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.75	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.75	gold quality
caudate nucleus	UBERON:0001873	99.74	gold quality
nucleus accumbens	UBERON:0001882	99.73	gold quality
mucosa of transverse colon	UBERON:0004991	99.73	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.73	gold quality
heart	UBERON:0000948	99.72	gold quality
primary visual cortex	UBERON:0002436	99.72	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.72	gold quality
cingulate cortex	UBERON:0003027	99.72	gold quality
anterior cingulate cortex	UBERON:0009835	99.72	gold quality
putamen	UBERON:0001874	99.71	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.71	gold quality
colonic mucosa	UBERON:0000317	99.70	gold quality
ileal mucosa	UBERON:0000331	99.70	gold quality
frontal cortex	UBERON:0001870	99.70	gold quality
endometrium epithelium	UBERON:0004811	99.69	gold quality
jejunal mucosa	UBERON:0000399	99.68	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-8410	yes	48.13
E-MTAB-10042	yes	16.72
E-MTAB-7316	yes	9.95
E-MTAB-7249	no	3418.74
E-HCAD-4	no	1919.28
E-CURD-77	no	1399.02
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETS1, FASTKD5, GABPA, HIF1A, NFE2L2, PPARGC1A, SP1, TRPV4

miRNA regulators (miRDB)

5 targeting COX4I1, 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-3180-5P	99.82	69.12	2422
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-374B-3P	98.63	68.24	1360
HSA-MIR-3622B-5P	94.62	64.58	835

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 23.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 19)

• study points to a role for surfeit 1(SURF1) in promoting the association of cytochrome c oxidase II with the cytochrome c oxidase I.cytochrome c oxidase subunit 4.cytochrome c oxidase subunit 5A subassembly (PMID:14607829)
• Under conditions of reduced oxygen availability, hypoxia-inducible factor 1 reciprocally regulates COX4 subunit expression by activating transcription of the genes encoding COX4-2 and LON, a mitochondrial protease that is required for COX4-1 degradation. (PMID:17418790)
• Data found that subunits Cox6a, Cox6b and Cox7a assembled into pre-existing complex IV, while Cox4-1 and Cox6c subunits assembled into subcomplexes that may represent rate-limiting intermediates. (PMID:19843159)
• Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 4 (PMID:20307258)
• Studies suggest a model that links cell signaling with the phosphorylation state of Cytochrome c (Cytc) and cytochrome c oxidase (COX). (PMID:21771582)
• Studies suggest that the main function of nuclear encoded subunits of cytochrome c oxidase appears to be “only” to control the activity of the mitochondrial subunits. (PMID:21802404)
• COX activity (electron transport complex IV) is reduced by 29% in maternal history of Alzheimer’s disease compared to normal controls, and by 30% compared to paternal history of Alzheimer’s disease. (PMID:21841246)
• Studies indicate that nitric oxide (NO) inhibition of cytochrome c oxidase (CcOX) is rapid and reversible and may occur in competition with oxygen. (PMID:21939634)
• Studies indicate that the mechanism for proton pumping in cytochrome c oxidase is based on an electrostatic analysis of a kinetic experiment for the O to E transition. (PMID:21978537)
• Studies indicate that the cytochrome oxidase enzyme-substrate (ES) Michaelis complex of cell respiration, the dioxygen adduct of heme a(3), which he termed Compound A. (PMID:22079200)
• COXIV mRNA (1.6 fold; P<0.01) and COXIV protein expression (1.5 fold; P<0.05) were increased by training but COXIV protein expression was decreased (20%; P<0.01) by acute exercise pre- and post-training. (PMID:23285255)
• We provide evidence that COX4-1 controls BMI1 expression via a redox mechanism (PMID:25726526)
• COX4I1 variant K101N was identified in a patient with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia. (PMID:28766551)
• This cohort study showed that the COX411 gene was down regulation between patients with idiopathic Parkinson disease and controls (PMID:28916538)
• In case of myocardial insufficiency and dilated cardiomyopathy, decreased expression of COX 4 results in an impaired CytOx activity. Higher enzymatic activity but equal oxygen consumption contribute to the pathophysiology of the myocardial insufficiency and appears as an indicator of oxidative stress. This kind of dysregulation should be in the focus for the development of diagnostic and therapy procedures (PMID:30223867)
• Upregulation of COX4-2 via HIF-1alpha in Mitochondrial COX4-1 Deficiency. (PMID:33672589)
• Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency. (PMID:35456968)
• The ratio of cytochrome c oxidase subunit 4 isoform 4I1 and 4I2 mRNA is changed in permanent atrial fibrillation. (PMID:38149324)
• Cytochrome c oxidase IV isoform 1 (COX4-1) regulates the proliferation, migration and invasion of trophoblast cells via modulating mitochondrial function. (PMID:38718733)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cox4i1	ENSDARG00000032970
mus_musculus	Cox4i1	ENSMUSG00000031818
rattus_norvegicus	Cox4i1	ENSRNOG00000017817
drosophila_melanogaster	COX4	FBGN0032833
drosophila_melanogaster	COX4L	FBGN0033020
caenorhabditis_elegans	cox-4	WBGENE00012354

Paralogs (1): COX4I2 (ENSG00000131055)

Protein

Protein identifiers

Cytochrome c oxidase subunit 4 isoform 1, mitochondrial — P13073 (reviewed: P13073)

Alternative names: Cytochrome c oxidase polypeptide IV, Cytochrome c oxidase subunit IV isoform 1

All UniProt accessions (7): P13073, H3BN72, H3BNI5, H3BNV9, H3BPG0, H3BPR4, Q86WV2

UniProt curated annotations — full annotation on UniProt →

Function. Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.

Subunit / interactions. Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and COXFA4, which are encoded in the nuclear genome. The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)). Interacts with AFG1L. Interacts with PHB2; the interaction decreases in absence of SPHK2. Interacts with ABCB7; this interaction allows the regulation of cellular iron homeostasis and cellular reactive oxygen species (ROS) levels in cardiomyocytes. Interacts with FLVCR2; this interaction occurs in the absence of heme and is disrupted upon heme binding. Interacts with IRGC.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Ubiquitous.

Disease relevance. Mitochondrial complex IV deficiency, nuclear type 16 (MC4DN16) [MIM:619060] An autosomal recessive mitochondrial disorder with onset in infancy and variable manifestations. MC4DN16 features include feeding difficulties, poor overall growth, short stature, microcephaly, developmental regression, severe hypotonia, and seizures. Cerebral and cerebellar atrophy, and abnormal lesions in the basal ganglia can be observed on brain imaging. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Energy metabolism; oxidative phosphorylation.

Similarity. Belongs to the cytochrome c oxidase IV family.

RefSeq proteins (6): NP_001305715, NP_001305717, NP_001305723, NP_001305726, NP_001305731, NP_001852* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004203	Cyt_c_oxidase_su4_fam	Family
IPR013288	Cyt_c_oxidase_su4	Family
IPR036639	Cyt_c_oxidase_su4_sf	Homologous_superfamily

Pfam: PF02936

UniProt features (17 total): modified residue 8, sequence variant 4, topological domain 2, transit peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9I6F	ELECTRON MICROSCOPY	2.95
9I7U	ELECTRON MICROSCOPY	3.15
5Z62	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13073-F1	89.29	0.84

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 (8): 60, 60, 67, 29, 29, 53, 56, 58

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-611105	Respiratory electron transport
R-HSA-9707564	Cytoprotection by HMOX1
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-9864848	Complex IV assembly

MSigDB gene sets: 319 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, MORF_MBD4, MORF_RAB5A, MORF_UBE2I, MORF_HDAC1, MORF_RAD21, HSIAO_HOUSEKEEPING_GENES, TGACCTY_ERR1_Q2, MORF_PSMC2, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, MORF_SKP1A, NIKOLSKY_BREAST_CANCER_16Q24_AMPLICON, GOBP_OXIDATIVE_PHOSPHORYLATION, MORF_CTBP1

GO Biological Process (6): generation of precursor metabolites and energy (GO:0006091), mitochondrial electron transport, cytochrome c to oxygen (GO:0006123), response to nutrient (GO:0007584), cellular respiration (GO:0045333), oxidative phosphorylation (GO:0006119), proton transmembrane transport (GO:1902600)

GO Molecular Function (2): cytochrome-c oxidase activity (GO:0004129), protein binding (GO:0005515)

GO Cellular Component (8): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial intermembrane space (GO:0005758), cytosol (GO:0005829), membrane (GO:0016020), mitochondrial membrane (GO:0031966), respiratory chain complex IV (GO:0045277)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Transcriptional Regulation by TP53	1
Aerobic respiration and respiratory electron transport	1
Cellular response to chemical stress	1
Metabolism of proteins	1
Respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
mitochondrial envelope	2
metabolic process	1
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
response to nutrient levels	1
response to chemical	1
energy derivation by oxidation of organic compounds	1
aerobic respiration	1
proton motive force-driven ATP synthesis	1
monoatomic cation transmembrane transport	1
electron transfer activity	1
proton transmembrane transporter activity	1
oxidoreduction-driven active transmembrane transporter activity	1
oxidoreductase activity, acting on a heme group of donors	1
active monoatomic ion transmembrane transporter activity	1
binding	1
nuclear lumen	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
organelle envelope lumen	1
mitochondrion	1
organelle membrane	1
cytochrome complex	1
respiratory chain complex	1
transmembrane transporter complex	1
oxidoreductase complex	1

Protein interactions and networks

STRING

3193 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COX4I1	COX5A	P20674	992
COX4I1	MT-CO1	P00395	975
COX4I1	EMC8	O43402	964
COX4I1	COX5B	P10606	935
COX4I1	MT-CO2	P00403	901
COX4I1	UQCRC2	P22695	867
COX4I1	COX6B1	P14854	856
COX4I1	COX6A1	P12074	853
COX4I1	SDHA	P31040	826
COX4I1	CYCS	P00001	821
COX4I1	UQCRH	P07919	820
COX4I1	HIGD1A	Q9Y241	817
COX4I1	COX6A2	Q02221	801
COX4I1	TFAM	Q00059	796
COX4I1	CASP3	P42574	793

IntAct

137 interactions, top by confidence:

A	B	Type	Score
SDCBP	COX4I1	psi-mi:“MI:0915”(physical association)	0.670
COX4I1	SDCBP	psi-mi:“MI:0915”(physical association)	0.670
RAC1	COX6C	psi-mi:“MI:0914”(association)	0.640
UQCRQ	COX7A2L	psi-mi:“MI:0914”(association)	0.640
UQCRB	COX7A2L	psi-mi:“MI:0914”(association)	0.640
COA3	MT-CO1	psi-mi:“MI:0914”(association)	0.610
COX4I1	DBT	psi-mi:“MI:0914”(association)	0.560
KLF11	COX4I1	psi-mi:“MI:0915”(physical association)	0.560
MT-CO2	COX6C	psi-mi:“MI:0915”(physical association)	0.560
COX4I1	DBT	psi-mi:“MI:0915”(physical association)	0.560
COX4I1	MT-CO1	psi-mi:“MI:0915”(physical association)	0.560
MT-CO1	COX4I1	psi-mi:“MI:0915”(physical association)	0.560
COX5A	COX7A2L	psi-mi:“MI:0914”(association)	0.530
COX5B	COX7A2L	psi-mi:“MI:0914”(association)	0.530
TIMM21	TIMM23	psi-mi:“MI:0914”(association)	0.500
COX7A2	COX4I1	psi-mi:“MI:0914”(association)	0.480
HSPD1	COX4I1	psi-mi:“MI:0403”(colocalization)	0.480
env	APP	psi-mi:“MI:0914”(association)	0.460
AIFM1	HAX1	psi-mi:“MI:2364”(proximity)	0.420
HTRA2	HAX1	psi-mi:“MI:2364”(proximity)	0.420
UBE2O	COX4I1	psi-mi:“MI:0915”(physical association)	0.400
TBCK	COX4I1	psi-mi:“MI:0915”(physical association)	0.400
ATRX	COX4I1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (599): SDCBP (Two-hybrid), COX4I1 (Affinity Capture-MS), ECHS1 (Affinity Capture-MS), DBT (Affinity Capture-MS), C7orf55 (Affinity Capture-MS), GLDC (Affinity Capture-MS), ALDOA (Co-fractionation), BCAP29 (Co-fractionation), BCAP31 (Co-fractionation), CISD2 (Co-fractionation), COX4I1 (Co-fractionation), COX4I1 (Co-fractionation), COX4I1 (Co-fractionation), COX4I1 (Co-fractionation), COX4I1 (Co-fractionation)

ESM2 similar proteins: O13082, O13085, O46577, O46578, O46579, O46580, O46581, O46584, O46585, O46586, O64725, P00423, P06810, P07471, P10817, P10818, P10888, P12074, P13073, P13183, P19783, P24311, P32799, P43023, P43024, P56393, P80431, P80971, Q02221, Q08CE7, Q0MQC7, Q20779, Q28ED6, Q4R648, Q5R9K2, Q5RC38, Q5RK28, Q5XG64, Q810Q5, Q8TF08

Diamond homologs: O46577, O46578, O46579, O46580, O46581, O46582, O46584, O46585, O46586, O46587, O46588, O46589, O46590, P00423, P10888, P13073, P19783, P80971, Q91W29, Q91Y94, Q95283, Q96KJ9, Q9I8U0, Q9TTT8, O74988, O93980, P00424, P00425, P06810

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
FASTKD5	“up-regulates quantity by expression”	COX4I1	“transcriptional regulation”
PPARGC1A	“up-regulates quantity by expression”	COX4I1	“transcriptional regulation”
COX4I1	up-regulates	Oxidative_phosphorylation
COX4I1	“form complex”	“Cytochrome c oxidase-Mitochondrial respiratory chain complex IV”	binding
“MITRAC complex”	“up-regulates quantity”	COX4I1	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 150 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	18	39.9×	3e-22
Cytoprotection by HMOX1	14	25.0×	4e-14
TP53 Regulates Metabolic Genes	14	17.6×	6e-12
Respiratory electron transport	19	17.6×	2e-16
Mitochondrial protein degradation	13	14.4×	6e-10

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, cytochrome c to oxygen	14	83.1×	4e-22
cellular respiration	13	43.5×	6e-16
mitochondrial respiratory chain complex IV assembly	5	24.2×	4e-04
generation of precursor metabolites and energy	5	13.3×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	31
Likely benign	2
Benign	3

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
834062	NM_001861.6(COX4I1):c.303_304delinsTT (p.Lys101_Thr102delinsAsnSer)	Pathogenic
834063	NM_001861.6(COX4I1):c.454C>A (p.Pro152Thr)	Pathogenic

SpliceAI

1106 predictions. Top by Δscore:

Variant	Effect	Δscore
16:85799060:CTTA:C	donor_loss	1.0000
16:85799061:TTA:T	donor_loss	1.0000
16:85799063:ACCAG:A	donor_loss	1.0000
16:85799064:C:CT	donor_loss	1.0000
16:85799858:G:GT	donor_gain	1.0000
16:85804935:A:AG	acceptor_gain	1.0000
16:85804936:G:GG	acceptor_gain	1.0000
16:85804936:GAA:G	acceptor_gain	1.0000
16:85804936:GAAA:G	acceptor_gain	1.0000
16:85805089:G:GT	donor_gain	1.0000
16:85805090:A:G	donor_gain	1.0000
16:85805095:A:T	donor_gain	1.0000
16:85805098:GTCGA:G	donor_gain	1.0000
16:85805101:GAGT:G	donor_gain	1.0000
16:85805103:GT:G	donor_gain	1.0000
16:85805105:G:GG	donor_gain	1.0000
16:85805147:G:GT	donor_gain	1.0000
16:85805731:A:AG	acceptor_gain	1.0000
16:85805732:G:GG	acceptor_gain	1.0000
16:85805732:GT:G	acceptor_gain	1.0000
16:85805732:GTGT:G	acceptor_gain	1.0000
16:85805861:TATGG:T	donor_loss	1.0000
16:85805862:ATGGT:A	donor_loss	1.0000
16:85805865:G:C	donor_loss	1.0000
16:85805865:G:GG	donor_gain	1.0000
16:85805866:TGA:T	donor_loss	1.0000
16:85805867:GAG:G	donor_loss	1.0000
16:85799059:GCTT:G	donor_loss	0.9900
16:85799063:A:AC	donor_gain	0.9900
16:85799064:C:CC	donor_gain	0.9900

AlphaMissense

1135 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:85805747:T:C	F86L	0.995
16:85805749:C:A	F86L	0.995
16:85805749:C:G	F86L	0.995
16:85806844:G:C	W160C	0.986
16:85806844:G:T	W160C	0.986
16:85806865:G:C	W167C	0.986
16:85806865:G:T	W167C	0.986
16:85805826:G:A	G112D	0.984
16:85806863:T:A	W167R	0.984
16:85806863:T:C	W167R	0.984
16:85805825:G:C	G112R	0.983
16:85805071:T:A	W70R	0.982
16:85805071:T:C	W70R	0.982
16:85805789:T:A	W100R	0.982
16:85805789:T:C	W100R	0.982
16:85806842:T:A	W160R	0.980
16:85806842:T:C	W160R	0.980
16:85805805:G:A	G105D	0.976
16:85805073:G:C	W70C	0.974
16:85805073:G:T	W70C	0.974
16:85805849:T:A	W120R	0.974
16:85805849:T:C	W120R	0.974
16:85806786:A:C	Q141P	0.974
16:85805739:G:C	R83P	0.973
16:85805756:A:C	S89R	0.972
16:85805758:C:A	S89R	0.972
16:85805758:C:G	S89R	0.972
16:85806864:G:C	W167S	0.969
16:85805794:G:C	K101N	0.968
16:85805794:G:T	K101N	0.968

dbSNP variants (sampled 300 via entrez): RS1000212372 (16:85806770 G>A,C), RS1000462389 (16:85799606 A>C), RS1000528952 (16:85806654 C>A,T), RS1000767125 (16:85800282 C>T), RS1000834522 (16:85799441 C>A,G,T), RS1000931679 (16:85800387 C>G), RS1001140704 (16:85802847 T>G), RS1001199720 (16:85799643 G>A,T), RS1001649364 (16:85799813 C>A), RS1002812663 (16:85802021 G>C,T), RS1002871843 (16:85800442 C>A,T), RS1003042089 (16:85806393 C>A,T), RS1003092639 (16:85798126 T>C,G), RS1003215797 (16:85806055 C>G), RS1003262940 (16:85805366 A>T)

Disease associations

OMIM: gene MIM:123864 | disease phenotypes: MIM:619060, MIM:220110

GenCC curated gene-disease

Disease	Classification	Inheritance
cytochrome-c oxidase deficiency disease	Supportive	Autosomal recessive
mitochondrial complex IV deficiency, nuclear type 16	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mitochondrial disease	Limited	AR
Leigh syndrome	Limited	AR

Mondo (4): mitochondrial complex IV deficiency, nuclear type 16 (MONDO:0033651), mitochondrial disease (MONDO:0044970), mitochondrial complex IV deficiency, nuclear type 1 (MONDO:0700250), (MONDO:0009068)

Orphanet (1): Mitochondrial disease (Orphanet:68380)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000426	Prominent nasal bridge
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001336	Myoclonus
HP:0001508	Failure to thrive
HP:0001885	Short 2nd toe
HP:0002007	Frontal bossing
HP:0002059	Cerebral atrophy
HP:0002151	Increased circulating lactate concentration
HP:0002376	Developmental regression
HP:0002421	Poor head control
HP:0002490	Increased CSF lactate
HP:0002521	Hypsarrhythmia
HP:0002750	Delayed skeletal maturation
HP:0003221	Chromosomal breakage induced by crosslinking agents
HP:0004322	Short stature
HP:0004325	Decreased body weight
HP:0005643	Short 3rd toe
HP:0007083	Hyperactive patellar reflex
HP:0008093	Short 4th toe
HP:0008347	Decreased activity of mitochondrial complex IV
HP:0009237	Short 5th finger
HP:0011097	Epileptic spasm
HP:0011917	Short 5th toe
HP:0033503	Elevated CSF fumarate concentration

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001859_7	Thiazide-induced adverse metabolic effects in hypertensive patients	7.000000e-06
GCST002772_17	Leprosy	4.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066293 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.35	Kd	443.2	nM	CHEMBL5653589
6.35	ED50	443.2	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148128: Binding affinity to human COX4I1 incubated for 45 mins by Kinobead based pull down assay	kd	0.4432	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
Arsenic Trioxide	decreases expression, decreases reaction, increases expression	2
Carbonyl Cyanide m-Chlorophenyl Hydrazone	decreases expression, increases reaction, affects cotreatment, decreases reaction, increases degradation	2
Doxorubicin	decreases expression, decreases reaction	2
Glucose	affects cotreatment, decreases expression, increases expression	2
Rotenone	affects reaction, increases expression	2
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
metoprine	decreases expression	1
cobaltiprotoporphyrin	decreases reaction, increases expression	1
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid	increases expression	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects binding, increases reaction	1
sodium bichromate	increases expression	1
8-bromocyclic GMP	increases expression, decreases reaction	1
mono-(2-ethylhexyl)phthalate	affects cotreatment, decreases reaction, increases degradation, increases reaction	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
gossypol acetic acid	affects reaction, decreases expression	1
tin protoporphyrin IX	increases expression, increases reaction, decreases reaction	1
ebselen	increases expression	1
1-methyl-4-phenyl-2,3-dihydropyridinium	decreases expression	1
4-phenylbutyric acid	decreases expression, decreases reaction	1
perfluorooctane sulfonic acid	increases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, increases expression	1
1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one	decreases reaction, increases expression	1
chloropicrin	increases expression	1
OSW 1	increases expression	1
S-nitro-N-acetylpenicillamine	decreases reaction, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651170	Binding	Binding affinity to human COX4I1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT03384420	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety and Therapeutic Effects of Transplantation of MNV-BM-BLD in Pediatric Patients With Pearson Syndrome
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy
NCT00786539	Not specified	COMPLETED	Mitochondria Inborn Errors of Metabolism and ANT Defects in Mitochondria Diseases
NCT00829270	Not specified	COMPLETED	Economic and Medical Evaluation of the Whole Mitochondrial DNA Screening by Surveyor and Mitochips Techniques
NCT00831948	Not specified	UNKNOWN	Identification of Large-Scale Mutations of POLG Gene by QMPSF in Patients With Mitochondrial DNA Instability.
NCT01001585	Not specified	TERMINATED	Anesthetic Effects in Mitochondrial Disease
NCT01148550	Not specified	SUSPENDED	Longitudinal Study of Mitochondrial Hepatopathies