MT-CO3

Summary

MT-CO3 (mitochondrially encoded cytochrome c oxidase III, HGNC:7422) is a protein-coding gene on chromosome mitochondria, encoding Cytochrome c oxidase subunit 3 (P00414). Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.

Predicted to contribute to cytochrome-c oxidase activity. Involved in respiratory chain complex IV assembly. Located in mitochondrial membrane. Part of respiratory chain complex IV. Implicated in MELAS syndrome.

Source: NCBI Gene 4514 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +4 more curated relationships
• Clinical variants (ClinVar): 172 total — 5 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 152
• Druggable target: yes

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7422
Approved symbol	MT-CO3
Name	mitochondrially encoded cytochrome c oxidase III
Location	mitochondria
Locus type	gene with protein product
Status	Approved
Aliases	COX3, COIII, CO3
Ensembl gene	ENSG00000198938
Ensembl biotype	protein_coding
OMIM	516050
Entrez	4514

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000362079

RefSeq mRNA: 0 — MANE Select: None

Canonical transcript exons

ENST00000362079 — 1 exons

Exon	Start	End
ENSE00001608952	9207	9990

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 100.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.4122 / max 597.0157, expressed in 1021 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194901	3.4122	1021

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
zone of skin	UBERON:0000014	100.00	gold quality
endocervix	UBERON:0000458	100.00	gold quality
rectum	UBERON:0001052	100.00	gold quality
transverse colon	UBERON:0001157	100.00	gold quality
mucosa of stomach	UBERON:0001199	100.00	gold quality
skin of abdomen	UBERON:0001416	100.00	gold quality
skin of leg	UBERON:0001511	100.00	gold quality
temporal lobe	UBERON:0001871	100.00	gold quality
amygdala	UBERON:0001876	100.00	gold quality
Ammon’s horn	UBERON:0001954	100.00	gold quality
apex of heart	UBERON:0002098	100.00	gold quality
subcutaneous adipose tissue	UBERON:0002190	100.00	gold quality
left testis	UBERON:0004533	100.00	gold quality
right testis	UBERON:0004534	100.00	gold quality
mucosa of transverse colon	UBERON:0004991	100.00	gold quality
thoracic mammary gland	UBERON:0005200	100.00	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	100.00	gold quality
right atrium auricular region	UBERON:0006631	100.00	gold quality
metanephros cortex	UBERON:0010533	100.00	gold quality
Brodmann (1909) area 9	UBERON:0013540	100.00	gold quality
granulocyte	CL:0000094	99.99	gold quality
uterine cervix	UBERON:0000002	99.99	gold quality
pituitary gland	UBERON:0000007	99.99	gold quality
adult mammalian kidney	UBERON:0000082	99.99	gold quality
intestine	UBERON:0000160	99.99	gold quality
prefrontal cortex	UBERON:0000451	99.99	gold quality
heart	UBERON:0000948	99.99	gold quality
brain	UBERON:0000955	99.99	gold quality
cerebral cortex	UBERON:0000956	99.99	gold quality
vagina	UBERON:0000996	99.99	gold quality

Single-cell (SCXA)

Detected in 89 experiment(s), a significant marker in 46.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	57772.04
E-GEOD-137537	yes	53027.47
E-GEOD-124263	yes	52034.64
E-MTAB-6505	yes	49344.71
E-CURD-88	yes	47811.15
E-CURD-46	yes	46021.78
E-MTAB-6701	yes	39486.04
E-MTAB-6308	yes	39345.83
E-MTAB-10290	yes	37087.26
E-MTAB-8271	yes	36051.96
E-MTAB-7407	yes	35445.70
E-MTAB-10885	yes	34143.46
E-HCAD-13	yes	33474.61
E-MTAB-8207	yes	32653.42
E-MTAB-8322	yes	32134.62

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 17)

• Data show that both normal and mutant alpha-synuclein specifically interact with the mitochondrial complex IV enzyme, cytochrome C oxidase (COX). (PMID:12059041)
• A mitochondrial DNA microdeletion removes the termination codon for MTATP6 and sets MTCO3 immediately in frame. (PMID:12915481)
• Mutations in mtDNA-encoded cytochrome c oxidase subunit III genes causing isolated myopathy or severe encephalomyopathy. (PMID:16288875)
• a MELAS syndrome Korean family harbor homoplasmic missense mutation in mitochondrial genom, which confers pathogenicity (Phe251Leu) (PMID:18587274)
• The total mtDNA major arc deletion level was greater than the common deletion level in COX 3-deficient spiral ganglion cells. (PMID:20085441)
• a novel heteroplasmic missense mitochondrial mutation at nucleotide 9478 in COX3 gene in patients with Leigh syndrome (PMID:20525945)
• A novel COX III subunit single base pair deletion is associated with a high number (45%) of COX-negative muscle fibers in a patient with severe rhabdomyolysis but no family history of neuromuscular disorder. (PMID:21163656)
• A novel heteroplasmic missense mitochondrial mutation (m.9387 G>A) in COXIII gene found in 3 asthenospermic patients from Tunisia. (PMID:23645088)
• A novel COIII gene m.9588G>A mutation was found in the mtDNA sperm’s in all asthenozoospermic patients and was absent in the normozoospermic and in fertile men. (PMID:24550096)
• this is the first study showing to demonstrate that aa72-117 in HBx is the key region for binding with COXIII. (PMID:25483779)
• Lack of Cox3 limits the biosynthesis of COX but does not alter the structure of the enzyme. (PMID:25588698)
• novel heteroplasmic mutation m.9276G>C in the mitochondrial COIII gene, detected in mtDNA extracted from leukocytes of a mother and her two daughters indicating that this mutation is maternally transmitted (PMID:25701779)
• There was a significant association of cytochrome c oxidase III 15bp deletion with human male infertility. (PMID:26712170)
• The T9861C Mutation in the mtDNA-Encoded Cytochrome C Oxidase Subunit III Gene Occurs in High Frequency but with Unequal Distribution in the Alzheimer’s Disease Brain. (PMID:31561357)
• HIGD2A is Required for Assembly of the COX3 Module of Human Mitochondrial Complex IV. (PMID:32317297)
• Whole mitochondrial genome analysis in Chinese patients with keratoconus. (PMID:34012229)
• A lack of a definite correlation between male sub-fertility and single nucleotide polymorphisms in sperm mitochondrial genes MT-CO3, MT-ATP6 and MT-ATP8. (PMID:36066780)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mt-co3	ENSDARG00000063912
mus_musculus	mt-Co3	ENSMUSG00000064358
rattus_norvegicus	Mt-co3	ENSRNOG00000030700
drosophila_melanogaster	mt:CoIII	FBGN0013676
caenorhabditis_elegans		WBGENE00010962

Protein

Protein identifiers

Cytochrome c oxidase subunit 3 — P00414 (reviewed: P00414)

Alternative names: Cytochrome c oxidase polypeptide III

All UniProt accessions (2): P00414, Q7GIM7

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)).

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Leber hereditary optic neuropathy (LHON) [MIM:535000] A maternally inherited form of Leber hereditary optic neuropathy, a mitochondrial disease resulting in bilateral painless loss of central vision due to selective degeneration of the retinal ganglion cells and their axons. The disorder shows incomplete penetrance and male predominance. Cardiac conduction defects and neurological defects have also been described in some LHON patients. LHON results from primary mitochondrial DNA mutations affecting the respiratory chain complexes. The disease is caused by variants affecting the gene represented in this entry. Mitochondrial complex IV deficiency (MT-C4D) [MIM:220110] A disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Features include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development and intellectual disability. Some affected individuals manifest a fatal hypertrophic cardiomyopathy resulting in neonatal death. A subset of patients manifest Leigh syndrome. The disease is caused by variants affecting the gene represented in this entry. Recurrent myoglobinuria mitochondrial (RM-MT) [MIM:550500] Recurrent myoglobinuria is characterized by recurrent attacks of rhabdomyolysis (necrosis or disintegration of skeletal muscle) associated with muscle pain and weakness, and followed by excretion of myoglobin in the urine. The gene represented in this entry may be involved in disease pathogenesis.

Similarity. Belongs to the cytochrome c oxidase subunit 3 family.

RefSeq proteins (0): (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000298	Cyt_c_oxidase-like_su3	Domain
IPR013833	Cyt_c_oxidase_su3_a-hlx	Homologous_superfamily
IPR024791	Cyt_c/ubiquinol_Oxase_su3	Family
IPR033945	Cyt_c_oxase_su3_dom	Domain
IPR035973	Cyt_c_oxidase_su3-like_sf	Homologous_superfamily

Pfam: PF00510

Catalyzed reactions (Rhea), 1 shown:

• 4 Fe(II)-[cytochrome c] + O2 + 8 H(+)(in) = 4 Fe(III)-[cytochrome c] + 2 H2O + 4 H(+)(out) (RHEA:11436)

UniProt features (26 total): sequence variant 9, topological domain 8, transmembrane region 7, chain 1, sequence conflict 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-P00414-F1	98.00	0.98

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-5419276	Mitochondrial translation termination
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-611105	Respiratory electron transport
R-HSA-9707564	Cytoprotection by HMOX1
R-HSA-9864848	Complex IV assembly

MSigDB gene sets: 376 (showing top): GOBP_RESPIRATORY_CHAIN_COMPLEX_IV_ASSEMBLY, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_ELECTRON_TRANSPORT_CHAIN, KEGG_HUNTINGTONS_DISEASE, GOCC_MITOCHONDRIAL_ENVELOPE, GOMF_PROTON_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOBP_CELLULAR_RESPIRATION, KEGG_ALZHEIMERS_DISEASE, GOBP_TRANSMEMBRANE_TRANSPORT, GOCC_CYTOCHROME_COMPLEX, GOCC_ORGANELLE_INNER_MEMBRANE, GOCC_TRANSPORTER_COMPLEX

GO Biological Process (6): mitochondrial electron transport, cytochrome c to oxygen (GO:0006123), respiratory chain complex IV assembly (GO:0008535), cellular respiration (GO:0045333), aerobic electron transport chain (GO:0019646), respiratory electron transport chain (GO:0022904), proton transmembrane transport (GO:1902600)

GO Molecular Function (3): cytochrome-c oxidase activity (GO:0004129), protein binding (GO:0005515), electron transfer activity (GO:0009055)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial membrane (GO:0031966), respiratory chain complex IV (GO:0045277), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Mitochondrial translation	1
Transcriptional Regulation by TP53	1
Aerobic respiration and respiratory electron transport	1
Cellular response to chemical stress	1
Respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
cytochrome complex assembly	1
energy derivation by oxidation of organic compounds	1
oxidative phosphorylation	1
aerobic respiration	1
respiratory electron transport chain	1
electron transport chain	1
cellular respiration	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
molecular_function	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
mitochondrial envelope	1
organelle membrane	1
cytochrome complex	1
respiratory chain complex	1
transmembrane transporter complex	1
oxidoreductase complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1711 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MT-CO3	MT-CO1	P00395	999
MT-CO3	MT-CO2	P00403	999
MT-CO3	MT-ATP6	P00846	978
MT-CO3	MT-ND5	P03915	975
MT-CO3	MT-ND6	P03923	966
MT-CO3	MT-ND4	P03905	964
MT-CO3	MT-ND2	P03891	963
MT-CO3	MT-CYB	P00156	960
MT-CO3	MT-ND4L	P03901	953
MT-CO3	MT-ND3	P03897	947
MT-CO3	MT-ATP8	P03928	946
MT-CO3	COX10	Q12887	890
MT-CO3	MT-ND1	P03886	876
MT-CO3	COX6B1	P14854	870
MT-CO3	COX15	Q7KZN9	848

IntAct

24 interactions, top by confidence:

A	B	Type	Score
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
SNCA	MT-CO3	psi-mi:“MI:0915”(physical association)	0.510
MT-CO3	SNCA	psi-mi:“MI:0915”(physical association)	0.510
HSPB2	MT-CO3	psi-mi:“MI:0915”(physical association)	0.370
ALG3	MT-CO3	psi-mi:“MI:0915”(physical association)	0.370
MT-CO3	E7	psi-mi:“MI:0915”(physical association)	0.370
RAC1	MT-CO3	psi-mi:“MI:0915”(physical association)	0.370
MT-CO3	KRAS	psi-mi:“MI:0915”(physical association)	0.370
MT-CO3		psi-mi:“MI:0915”(physical association)	0.370
COX6A1	COX7A2L	psi-mi:“MI:0914”(association)	0.350
COX4I1	COX7A2L	psi-mi:“MI:0914”(association)	0.350
COX7A1	GLS	psi-mi:“MI:0914”(association)	0.350
FFAR1	SLC12A8	psi-mi:“MI:0914”(association)	0.350
MFSD10	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NIPAL3	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC2A7	GPR89A	psi-mi:“MI:0914”(association)	0.350
SLC35A3	STXBP3	psi-mi:“MI:0914”(association)	0.350
SLC35E3	TP53I11	psi-mi:“MI:0914”(association)	0.350
COA3	TMEM223	psi-mi:“MI:0914”(association)	0.350
MT-CO2	NDUFA4	psi-mi:“MI:0914”(association)	0.350
HTT	TPP1	psi-mi:“MI:0914”(association)	0.350
CNTRL	ANKRD28	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (56): COX3 (Two-hybrid), COX3 (Two-hybrid), COX3 (Proximity Label-MS), COX3 (Affinity Capture-Western), COX3 (Affinity Capture-MS), COX3 (Affinity Capture-MS), COX3 (Affinity Capture-MS), COX3 (Affinity Capture-RNA), COX3 (Affinity Capture-MS), COX3 (Affinity Capture-MS), COX3 (Affinity Capture-MS), COX3 (Affinity Capture-MS), COX3 (Affinity Capture-MS), COX3 (Affinity Capture-MS), COX3 (Affinity Capture-MS)

ESM2 similar proteins: O03170, O21331, O21403, O21619, O47686, O47690, O47691, O47693, O47695, O47696, O47697, O47698, O47699, O47702, O47705, O47706, O47708, O47709, O48316, O48374, O79433, O79552, P00414, P00415, P00416, P05505, P18945, P24989, P48892, P68088, P68089, P68299, P92481, P92665, P92696, Q2I3F5, Q2I3G8, Q35539, Q35916, Q36455

Diamond homologs: B0FWD1, O03170, O03201, O21331, O21619, O47475, O47685, O47686, O47687, O47688, O47689, O47690, O47691, O47692, O47693, O47694, O47695, O47696, O47697, O47698, O47699, O47700, O47701, O47702, O47705, O47706, O47708, O47709, O47710, O48316, O48374, O63915, O79407, O79433, O79676, P00414, P00415, P00416, P00417, P00418

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MT-CO3	“form complex”	“Cytochrome c oxidase-Mitochondrial respiratory chain complex IV”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 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	7	66.6×	1e-09
Cytoprotection by HMOX1	5	38.4×	9e-06
TP53 Regulates Metabolic Genes	6	32.4×	2e-06
Respiratory electron transport	6	23.8×	9e-06

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, cytochrome c to oxygen	5	141.8×	6e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	5
Uncertain significance	82
Likely benign	35
Benign	39

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
430674	NC_012920.1(MT-TS1):m.6005_11222del	Pathogenic
590891	NC_012920.1(MT-CO3):m.9431_9432insA	Pathogenic
599026	NC_012920.1(MT-CO3):m.9429_9430insCCC	Pathogenic
599027	NC_012920.1(MT-CO3):m.9443_9444insTTT	Pathogenic
599028	NC_012920.1(MT-CO3):m.9273_9274insATC	Pathogenic
209213	NC_012920.1(MT-TY):m.5794_14876del	Likely pathogenic
590894	NC_012920.1(MT-CO3):m.9311_9312insGCA	Likely pathogenic
9654	NC_012920.1(MT-CO3):m.9487_9501del	Likely pathogenic
9655	NC_012920.1(MT-CO3):m.9952G>A	Likely pathogenic
9656	NC_012920.1(MT-CO3):m.9537dup	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1658 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
M:9723:T:C	F173L	0.999
M:9725:T:A	F173L	0.999
M:9725:T:G	F173L	0.999
M:9951:T:C	W249R	0.999
M:9375:T:C	W57R	0.998
M:9616:T:C	L137S	0.998
M:9816:C:G	H204D	0.998
M:9825:C:G	H207D	0.998
M:9924:T:C	W240R	0.998
M:9930:T:C	W242R	0.998
M:9378:T:C	W58R	0.997
M:9552:T:C	W116R	0.997
M:9616:T:G	L137W	0.997
M:9619:T:A	L138H	0.997
M:9795:T:C	F197L	0.997
M:9797:T:A	F197L	0.997
M:9797:T:G	F197L	0.997
M:9933:C:G	H243D	0.997
M:9936:T:C	F244L	0.997
M:9938:T:A	F244L	0.997
M:9938:T:G	F244L	0.997
M:9252:T:C	W16R	0.996
M:9462:T:C	F86L	0.996
M:9464:T:A	F86L	0.996
M:9464:T:G	F86L	0.996
M:9486:T:C	F94L	0.996
M:9488:C:A	F94L	0.996
M:9488:C:G	F94L	0.996
M:9762:T:C	F186L	0.996
M:9764:C:A	F186L	0.996

dbSNP variants (sampled 300 via entrez): RS1057516060 (MT:7373 A>G), RS1057516061 (MT:7496 T>C), RS1057516062 (MT:8418 T>C), RS1057516063 (MT:9166 T>C), RS1057516064 (MT:9237 G>A), RS1057518824 (MT:8084 A>G,T), RS1057520079 (MT:9091 A>G), RS1057520102 (MT:8816 A>G), RS1057520115 (MT:8260 T>C), RS1057520204 (MT:8943 C>T), RS1064597 (MT:8647 C>G), RS111033173 (MT:7468 C>A,T), RS111033319 (MT:7465 AC>A,ACC), RS111033324 (MT:7498 G>A), RS1116904 (MT:8027 G>A,T)

Disease associations

OMIM: gene MIM:516050 | disease phenotypes: MIM:256000, MIM:540000, MIM:535000, MIM:187500, MIM:220110, MIM:500009

GenCC curated gene-disease

Disease	Classification	Inheritance
Leber hereditary optic neuropathy	Supportive	Mitochondrial
cytochrome-c oxidase deficiency disease	Supportive	Autosomal recessive
hereditary recurrent myoglobinuria	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Leigh syndrome	Limited	MT
mitochondrial disease	Definitive	MT

Mondo (20): Leigh syndrome (MONDO:0009723), autosomal dominant spastic ataxia (MONDO:0017846), mitochondrial disease (MONDO:0044970), MELAS syndrome (MONDO:0010789), dilated cardiomyopathy (MONDO:0005021), venous thromboembolism (MONDO:0005399), intellectual disability (MONDO:0001071), epilepsy (MONDO:0005027), Leber hereditary optic neuropathy (MONDO:0010788), cerebellar ataxia (MONDO:0000437), sleep apnea syndrome (MONDO:0005296), hearing loss disorder (MONDO:0005365), nephrolithiasis (MONDO:0008171), acute liver failure (MONDO:0019542), oromandibular dystonia (MONDO:0019771)

Orphanet (12): Autosomal dominant spastic ataxia (Orphanet:316235), Leigh syndrome (Orphanet:506), Mitochondrial disease (Orphanet:68380), MELAS (Orphanet:550), Dilated cardiomyopathy (Orphanet:217604), Leber hereditary optic neuropathy (Orphanet:104), Rare ataxia (Orphanet:102002), Acute liver failure (Orphanet:90062), Oromandibular dystonia (Orphanet:93958), Tetralogy of Fallot (Orphanet:3303), Mitochondrial myopathy with reversible cytochrome C oxidase deficiency (Orphanet:254864), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

152 total (30 of 152 shown, HPO-id order):

HPO	Term
HP:0000044	Hypogonadotropic hypogonadism
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000097	Focal segmental glomerulosclerosis
HP:0000112	Nephropathy
HP:0000114	Proximal tubulopathy
HP:0000407	Sensorineural hearing impairment
HP:0000408	Progressive sensorineural hearing impairment
HP:0000467	Neck muscle weakness
HP:0000512	Abnormal electroretinogram
HP:0000519	Developmental cataract
HP:0000529	Progressive visual loss
HP:0000551	Color vision defect
HP:0000572	Visual loss
HP:0000576	Centrocecal scotoma
HP:0000580	Pigmentary retinopathy
HP:0000590	Progressive external ophthalmoplegia
HP:0000602	Ophthalmoplegia
HP:0000603	Central scotoma
HP:0000622	Blurred vision
HP:0000648	Optic atrophy
HP:0000649	Abnormality of visual evoked potentials
HP:0000709	Psychosis
HP:0000716	Depression
HP:0000726	Dementia
HP:0000736	Short attention span
HP:0000739	Anxiety
HP:0000751	Personality changes
HP:0000819	Diabetes mellitus
HP:0000821	Hypothyroidism

GWAS associations

0 associations (top):

MeSH disease descriptors (13)

Descriptor	Name	Tree numbers
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D004827	Epilepsy	C10.228.140.490
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
D017114	Liver Failure, Acute	C06.552.308.500.750
D017241	MELAS Syndrome	C05.651.460.620.520; C10.228.140.163.100.535; C10.228.140.300.275.500; C10.668.491.500.500.500; C14.907.253.329.500; C16.320.565.189.535; C18.452.132.100.535; C18.452.648.189.535; C18.452.660.560.620.520
D053040	Nephrolithiasis	C12.050.351.968.419.600; C12.050.351.968.967.249; C12.200.777.419.600; C12.200.777.967.249; C12.950.419.600; C12.950.967.249
D029242	Optic Atrophy, Hereditary, Leber	C10.292.700.225.500.400; C10.574.500.662.400; C11.270.564.400; C11.640.451.451.400; C16.320.290.564.400; C16.320.400.630.400; C18.452.660.670
D012891	Sleep Apnea Syndromes	C08.618.085.852; C10.886.425.800.750
D013771	Tetralogy of Fallot	C14.240.400.849; C14.280.400.849; C16.131.240.400.849
D054556	Venous Thromboembolism	C14.907.355.590.700

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066983 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2853826	MT-CO3, MT-ND3, MT-ND4, MT-ND4L, MT-ND5	3	2.00	1	efavirenz;lopinavir;Nucleoside and nucleotide reverse transcriptase inhibitors;ritonavir

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
5.58	Kd	2661	nM	CHEMBL5653589
5.58	ED50	2661	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	2148792: Binding affinity to human MT-CO3 incubated for 45 mins by Kinobead based pull down assay	kd	2.6607	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, increases abundance	4
beauvericin	decreases expression, affects cotreatment	3
enniatins	affects cotreatment, decreases expression	3
Atrazine	decreases expression	2
Plant Extracts	affects cotreatment, increases expression, decreases expression	2
Dronabinol	decreases expression, increases expression	2
Zidovudine	affects expression, increases expression	2
1-Methyl-4-phenylpyridinium	decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
2-hydroxyestradiol	increases expression	1
bisphenol A	decreases expression	1
di-n-octyl phthalate	decreases expression	1
4-hydroxyestradiol	increases expression	1
methylparaben	decreases expression	1
perfluorooctanoic acid	decreases expression	1
ochratoxin A	affects cotreatment, decreases expression	1
aflatoxin G1	affects cotreatment, increases expression	1
aflatoxin B2	affects cotreatment, increases expression	1
aflatoxin G2	affects cotreatment, increases expression	1
tris(chloroethyl)phosphate	increases abundance, increases expression	1
dimethoxyethyl phthalate	decreases expression	1
perfluorodecanoic acid	increases expression	1
1-methyl-4-phenyl-2,3-dihydropyridinium	decreases expression	1
arsenic trichloride	decreases expression, increases abundance	1
licochalcone B	decreases expression	1
Resveratrol	increases expression	1
Gemcitabine	decreases response to substance, decreases reaction	1
Adenosine Triphosphate	increases abundance	1
Arsenic	decreases expression, increases abundance	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
CHEMBL5651834	Binding	Binding affinity to human MT-CO3 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)

302 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
NCT01831934	PHASE4	COMPLETED	Responses to Influenza Vaccine in Patients With Mitochondrial Disorders (MELAS)
NCT00374465	PHASE4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	PHASE4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	PHASE4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	PHASE4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	PHASE4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	PHASE4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT03293524	PHASE3	COMPLETED	Efficacy & Safety Study of Bilateral IVT Injection of GS010 in LHON Subjects Due to the ND4 Mutation for up to 1 Year
NCT03406104	PHASE3	COMPLETED	RESCUE and REVERSE Long-term Follow-up
NCT07406854	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3, Multicenter, Randomized, Double-Masked, Sham-Controlled Clinical Trial for Leber’s Hereditary Optic Neuropathy (LHON) Associated With ND4 Mutation
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
NCT00333827	PHASE3	COMPLETED	Cell Therapy In Dilated Cardiomyopathy
NCT00505154	PHASE3	COMPLETED	Effect of Rosuvastatin on Left Ventricular Remodeling
NCT01223703	PHASE3	COMPLETED	PUFAs and Left Ventricular Function in Heart Failure
NCT01583114	PHASE3	TERMINATED	PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors
NCT01914081	PHASE3	UNKNOWN	Resveratrol: A Potential Anti- Remodeling Agent in Heart Failure, From Bench to Bedside
NCT02989181	PHASE3	UNKNOWN	Continues Positive Airway Pressure Treatment for Patients With Dilated Cardiomyopathy and Obstructive Sleep Apnea
NCT03439514	PHASE3	TERMINATED	A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT05849766	PHASE3	COMPLETED	Effect of Dapagliflozin on Cardiac Structure, Function and Secondary Mitral Regurgitation in Patients with Left Ventricle Dysfunction
NCT06250257	PHASE3	RECRUITING	Bromocriptine in Dilated Cardiomyopathy Among Women of Reproductive Age
NCT02176733	PHASE2	UNKNOWN	Trial of Cyclosporine in the Acute Phase of Leber Hereditary Optic Neuropathy
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
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