MT-ND2

Summary

MT-ND2 (mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 2, HGNC:7456) is a protein-coding gene on chromosome mitochondria, encoding NADH-ubiquinone oxidoreductase chain 2 (P03891). Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.

Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial inner membrane. Part of respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; multiple sclerosis; myocardial infarction; neurodegenerative disease (multiple); and urinary bladder cancer.

Source: NCBI Gene 4536 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Moderate, ClinGen) — +4 more curated relationships
• Clinical variants (ClinVar): 186 total — 1 likely-pathogenic
• Phenotypes (HPO): 105
• Druggable target: yes

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7456
Approved symbol	MT-ND2
Name	mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 2
Location	mitochondria
Locus type	gene with protein product
Status	Approved
Aliases	ND2, NAD2
Ensembl gene	ENSG00000198763
Ensembl biotype	protein_coding
OMIM	516001
Entrez	4536

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000361453

RefSeq mRNA: 0 — MANE Select: None

Canonical transcript exons

ENST00000361453 — 1 exons

Exon	Start	End
ENSE00001435686	4470	5511

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.99.

FANTOM5 (CAGE): breadth broad, TPM avg 0.5177 / max 16.9020, expressed in 250 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194852	0.5177	250

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adipose tissue	UBERON:0001013	99.99	gold quality
right uterine tube	UBERON:0001302	99.99	gold quality
left uterine tube	UBERON:0001303	99.99	gold quality
caudate nucleus	UBERON:0001873	99.99	gold quality
putamen	UBERON:0001874	99.99	gold quality
nucleus accumbens	UBERON:0001882	99.99	gold quality
substantia nigra	UBERON:0002038	99.99	gold quality
subcutaneous adipose tissue	UBERON:0002190	99.99	gold quality
cerebellar hemisphere	UBERON:0002245	99.99	gold quality
thoracic mammary gland	UBERON:0005200	99.99	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.99	gold quality
omental fat pad	UBERON:0010414	99.99	gold quality
metanephros cortex	UBERON:0010533	99.99	gold quality
lower esophagus	UBERON:0013473	99.99	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.99	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.99	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.99	gold quality
pituitary gland	UBERON:0000007	99.98	gold quality
zone of skin	UBERON:0000014	99.98	gold quality
endocervix	UBERON:0000458	99.98	gold quality
brain	UBERON:0000955	99.98	gold quality
right lobe of thyroid gland	UBERON:0001119	99.98	gold quality
left lobe of thyroid gland	UBERON:0001120	99.98	gold quality
transverse colon	UBERON:0001157	99.98	gold quality
fundus of stomach	UBERON:0001160	99.98	gold quality
body of stomach	UBERON:0001161	99.98	gold quality
mucosa of stomach	UBERON:0001199	99.98	gold quality
cortex of kidney	UBERON:0001225	99.98	gold quality
right adrenal gland	UBERON:0001233	99.98	gold quality
left adrenal gland	UBERON:0001234	99.98	gold quality

Single-cell (SCXA)

Detected in 63 experiment(s), a significant marker in 31.

Experiment	Marker?	Max mean expression
E-MTAB-7381	yes	40011.55
E-MTAB-6308	yes	29403.48
E-MTAB-8530	yes	22713.92
E-CURD-88	yes	22708.64
E-HCAD-5	yes	22178.67
E-CURD-98	yes	21524.26
E-MTAB-6505	yes	18123.09
E-MTAB-8884	yes	17288.51
E-MTAB-9435	yes	16898.92
E-GEOD-180759	yes	16150.36
E-MTAB-9467	yes	15821.90
E-HCAD-24	yes	14760.72
E-MTAB-8060	yes	14256.82
E-MTAB-10287	yes	12530.01
E-CURD-122	yes	12143.87

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 15)

• Novel mitochondrial DNA mutations in Parkinson’s disease. we report novel homoplasmic base changes. We were unable to detect heteroplasmic base changes. (PMID:12111463)
• Mutation T4681C disturbs the mitochondrial electron transport complex I assembly pathway and leads to Leigh syndrome. (PMID:16996290)
• results suggest that ND2-237 Leu/Met polymorphism is associated with hypertension and that modification of hypertension risk is dependent on alcohol consumption in middle-aged Japanese men (PMID:17510502)
• mitochondrial MTND2 polymorphism may increase susceptibility to nucleoside reverse transcriptase inhibitors associated peripheral neuropathy (PMID:17684475)
• modifies the effects of coffee consumption on blood pressure or the risk of hypertension (PMID:19667492)
• For Mt5178C genotypic men, alcohol consumption may reduce the risk of hyper-LDL cholesterolemia (PMID:21702983)
• The Mt5178 C/A genotype, which results in an amino acid polymorphism in NADH dehydrogenase subunit 2, may modify longitudinal changes in serum total cholesterol and high-density lipoprotein cholesterol levels in middle-aged Japanese men. (PMID:22351520)
• demethylation of the D-loop plays a key role in regulating ND2 expression during the initiation and/or progression of colorectal cancer. (PMID:22505229)
• This study did not show a correlation between ARMS2, C3, MT-NDH2, and CFH alleles in the development of choroid neovascularization associated with ocular histoplasmosis. (PMID:24612979)
• Study identified cancer-specific somatic variants in the ND2 and ND3 regions, and the presence of these mutated DNAs in the serum during the postoperative period accurately predicted poor prognoses in oral squamous cell carcinomas. (PMID:26179426)
• Data show no association between the mitochondrial 5178C/A polymorphism of NADH-dehydrogenase subunit 2 (ND2) gene with type-2 diabetes mellitus (T2DM), however, the polymorphism may affect the development of nephropathy and hypertension complications. (PMID:26663065)
• The C5263T single-nucleotide mutation of the mitochondrial ND2 gene was observed in 2 young coronary heart disease (CHD) patients in the case group. The premature CHD of these 2 patients followed a pattern of maternal inheritance. (PMID:28494837)
• gene variants not associated with total fertilization failure (PMID:29577757)
• Analysis of variants in mitochondrial genome and their putative pathogenicity in tuberculosis patients from Mizoram, North east India. (PMID:32652230)
• Impact of Mitochondrial Genetic Variants in ND1, ND2, ND5, and ND6 Genes on Sperm Motility and Intracytoplasmic Sperm Injection (ICSI) Outcomes. (PMID:33475980)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mt-nd2	ENSDARG00000063899
mus_musculus	mt-Nd2	ENSMUSG00000064345
rattus_norvegicus	Mt-nd2	ENSRNOG00000031033
drosophila_melanogaster	mt:ND2	FBGN0013680

Paralogs (2): MT-ND5 (ENSG00000198786), MT-ND4 (ENSG00000198886)

Protein

Protein identifiers

NADH-ubiquinone oxidoreductase chain 2 — P03891 (reviewed: P03891)

Alternative names: NADH dehydrogenase subunit 2

All UniProt accessions (2): P03891, Q7GXY9

UniProt curated annotations — full annotation on UniProt →

Function. Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. Essential for the catalytic activity and assembly of complex I.

Subunit / interactions. Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits. Interacts with TMEM242.

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. Alzheimer disease mitochondrial (AD-MT) [MIM:502500] Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Leigh syndrome (LS) [MIM:256000] An early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the complex I subunit 2 family.

RefSeq proteins (0): (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001750	ND/Mrp_TM	Domain
IPR003917	NADH_UbQ_OxRdtase_chain2	Family
IPR010933	NADH_DH_su2_C	Domain
IPR050175	Complex_I_Subunit_2	Family

Pfam: PF00361, PF06444

Catalyzed reactions (Rhea), 1 shown:

• a ubiquinone + NADH + 5 H(+)(in) = a ubiquinol + NAD(+) + 4 H(+)(out) (RHEA:29091)

UniProt features (33 total): sequence variant 22, transmembrane region 10, chain 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
9I4I	ELECTRON MICROSCOPY	2.63
9TI4	ELECTRON MICROSCOPY	2.66
9CWT	ELECTRON MICROSCOPY	3.44
5XTC	ELECTRON MICROSCOPY	3.7
5XTD	ELECTRON MICROSCOPY	3.7
5XTH	ELECTRON MICROSCOPY	3.9
5XTI	ELECTRON MICROSCOPY	17.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P03891-F1	95.15	0.94

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5419276	Mitochondrial translation termination
R-HSA-611105	Respiratory electron transport
R-HSA-6799198	Complex I biogenesis
R-HSA-9837999	Mitochondrial protein degradation

MSigDB gene sets: 318 (showing top): GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, TGACCTY_ERR1_Q2, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_ATP_BIOSYNTHETIC_PROCESS, GOBP_RESPONSE_TO_OXYGEN_LEVELS, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_BIOSYNTHETIC_PROCESS

GO Biological Process (7): response to hypoxia (GO:0001666), mitochondrial electron transport, NADH to ubiquinone (GO:0006120), aerobic respiration (GO:0009060), mitochondrial respiratory chain complex I assembly (GO:0032981), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), reactive oxygen species metabolic process (GO:0072593), proton transmembrane transport (GO:1902600)

GO Molecular Function (4): NADH dehydrogenase (ubiquinone) activity (GO:0008137), protein kinase binding (GO:0019901), ionotropic glutamate receptor binding (GO:0035255), protein binding (GO:0005515)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), respiratory chain complex I (GO:0045271), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Mitochondrial translation	1
Aerobic respiration and respiratory electron transport	1
Respiratory electron transport	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to stress	1
response to decreased oxygen levels	1
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
cellular respiration	1
NADH dehydrogenase complex assembly	1
mitochondrial respiratory chain complex assembly	1
mitochondrion	1
oxidative phosphorylation	1
proton motive force-driven ATP synthesis	1
metabolic process	1
monoatomic cation transmembrane transport	1
NADH dehydrogenase activity	1
electron transfer activity	1
proton transmembrane transporter activity	1
oxidoreduction-driven active transmembrane transporter activity	1
oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor	1
active monoatomic ion transmembrane transporter activity	1
kinase binding	1
glutamate receptor binding	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
NADH dehydrogenase complex	1
respiratory chain complex	1
transmembrane transporter complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2611 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MT-ND2	MT-ND6	P03923	999
MT-ND2	MT-ND1	P03886	999
MT-ND2	MT-ND4L	P03901	999
MT-ND2	MT-ND4	P03905	999
MT-ND2	MT-ND3	P03897	999
MT-ND2	MT-ND5	P03915	993
MT-ND2	MT-ATP6	P00846	968
MT-ND2	MT-CO3	P00414	963
MT-ND2	MT-CYB	P00156	960
MT-ND2	MT-CO1	P00395	958
MT-ND2	MT-CO2	P00403	944
MT-ND2	MT-ATP8	P03928	921
MT-ND2	PTGS1	P23219	882
MT-ND2	NDUFS1	P28331	871
MT-ND2	NDUFS8	O00217	870

IntAct

20 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
TIMMDC1	NDUFS8	psi-mi:“MI:0914”(association)	0.530
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
NDUFC2	NDUFS4	psi-mi:“MI:0914”(association)	0.530
MT-ND2	E6	psi-mi:“MI:0915”(physical association)	0.370
MT-ND2	STK11	psi-mi:“MI:0915”(physical association)	0.370
NDUFA11	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFA6	NDUFS8	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
FNDC4	MT-ND2	psi-mi:“MI:0914”(association)	0.350
NDUFA7	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFV3	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFB3	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFB5	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFB11	NDUFS8	psi-mi:“MI:0914”(association)	0.350

BioGRID (27): ND2 (Two-hybrid), ND2 (Affinity Capture-MS), ND2 (Affinity Capture-MS), ND2 (Affinity Capture-MS), ND2 (Affinity Capture-MS), ND2 (Affinity Capture-MS), ND2 (Affinity Capture-MS), SRC (Reconstituted Complex), ND2 (Affinity Capture-Western), GRIN1 (Affinity Capture-Western), ND2 (Affinity Capture-RNA), ND2 (Affinity Capture-MS), ND2 (Proximity Label-MS), ND2 (Proximity Label-MS), ND2 (Two-hybrid)

ESM2 similar proteins: O03166, O21409, O21798, O78680, O79428, O79671, P03891, P16673, P24970, P24972, P34187, P41297, P55780, P92660, P92691, Q2I3H3, Q2TGY2, Q32ZZ4, Q32ZZ9, Q330A0, Q330A4, Q330A5, Q330A7, Q330A8, Q330B1, Q330B3, Q330B4, Q330C4, Q330D8, Q330E4, Q330E6, Q330E9, Q330F2, Q330G8, Q330G9, Q330H1, Q330H3, Q34799, Q36451, Q38PS1

Diamond homologs: B0FWC6, O03166, O03197, O21001, O21326, O21398, O21409, O21798, O47434, O78748, O79428, O79671, O79875, P03891, P03892, P03893, P03894, P03895, P03896, P15549, P16673, P18937, P24970, P29867, P29868, P29869, P33503, P34848, P38599, P41297, P41305, P48653, P48905, P55780, P92476, P92660, P92691, Q00540, Q2I3H3, Q2TGY2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MT-ND2	“form complex”	“NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 20 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 I biogenesis	14	128.7×	2e-27
Respiratory electron transport	13	68.7×	1e-21
Aerobic respiration and respiratory electron transport	13	63.9×	2e-21

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	11	207.6×	5e-23
proton motive force-driven mitochondrial ATP synthesis	12	166.3×	1e-23
aerobic respiration	12	156.5×	1e-23
mitochondrial respiratory chain complex I assembly	7	151.4×	3e-13

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	76
Likely benign	53
Benign	52

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
9720	NC_012920.1(MT-ND2):m.4810G>A	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2193 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
M:4788:G:T	G107W	0.999
M:4809:T:C	W114R	0.999
M:5034:T:C	W189R	0.999
M:5247:T:C	F260L	0.999
M:5249:T:A	F260L	0.999
M:5249:T:G	F260L	0.999
M:4557:T:C	W30R	0.998
M:4866:T:C	W133R	0.998
M:5031:G:C	G188R	0.998
M:5031:G:T	G188W	0.998
M:4515:G:C	G16R	0.997
M:4563:G:C	G32R	0.997
M:4567:T:C	L33P	0.997
M:4570:A:T	E34V	0.997
M:4666:C:A	A66E	0.997
M:4788:G:C	G107R	0.997
M:4811:A:C	W114C	0.997
M:4811:A:T	W114C	0.997
M:4882:C:G	P138R	0.997
M:4963:G:A	G165D	0.997
M:4965:A:C	S166R	0.997
M:5017:C:G	S183W	0.997
M:5259:T:C	W264R	0.997
M:4536:A:C	S23R	0.996
M:4564:G:A	G32D	0.996
M:4719:T:C	W84R	0.996
M:4789:G:A	G107E	0.996
M:4962:G:C	G165R	0.996
M:5032:G:A	G188E	0.996
M:5244:G:C	G259R	0.996

dbSNP variants (sampled 300 via entrez): RS1057516057 (MT:3275 C>A,G,T), RS1057516058 (MT:3624 A>C,G), RS1057516059 (MT:4664 C>T), RS1057520057 (MT:5105 T>C), RS1057520067 (MT:4472 T>C), RS1057520173 (MT:3169 C>T), RS1057520201 (MT:4132 G>A), RS1117205 (MT:4104 A>G), RS1117207 (MT:4596 G>A), RS112161681 (MT:3116 C>T), RS11510098 (MT:4454 T>A,C,G), RS11510099 (MT:4506 A>G), RS118203884 (MT:4409 T>C), RS118203891 (MT:5874 T>C), RS118203892 (MT:5884 AT>A)

Disease associations

OMIM: gene MIM:516001 | disease phenotypes: MIM:256000, MIM:500009, MIM:535000

GenCC curated gene-disease

Disease	Classification	Inheritance
Leber hereditary optic neuropathy	Supportive	Mitochondrial
maternally-inherited Leigh syndrome	Supportive	Mitochondrial
mitochondrial complex I deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Leigh syndrome	Limited	MT
mitochondrial disease	Moderate	MT

Mondo (8): mitochondrial disease (MONDO:0044970), Leigh syndrome (MONDO:0009723), epilepsy (MONDO:0005027), congenital heart disease (MONDO:0005453), mitochondrial myopathy with reversible cytochrome C oxidase deficiency (MONDO:0010780), Leber hereditary optic neuropathy (MONDO:0010788), mitochondrial complex I deficiency (MONDO:0100133), maternally-inherited Leigh syndrome (MONDO:0016814)

Orphanet (5): Mitochondrial disease (Orphanet:68380), Leigh syndrome (Orphanet:506), Mitochondrial myopathy with reversible cytochrome C oxidase deficiency (Orphanet:254864), Leber hereditary optic neuropathy (Orphanet:104), Isolated complex I deficiency (Orphanet:2609)

HPO phenotypes

105 total (30 of 105 shown, HPO-id order):

HPO	Term
HP:0000091	Abnormal renal tubule morphology
HP:0000114	Proximal tubulopathy
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000529	Progressive visual loss
HP:0000543	Optic disc pallor
HP:0000551	Color vision defect
HP:0000572	Visual loss
HP:0000576	Centrocecal scotoma
HP:0000580	Pigmentary retinopathy
HP:0000597	Ophthalmoparesis
HP:0000603	Central scotoma
HP:0000618	Blindness
HP:0000622	Blurred vision
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000649	Abnormality of visual evoked potentials
HP:0000816	Abnormality of Krebs cycle metabolism
HP:0000817	Reduced eye contact
HP:0000819	Diabetes mellitus
HP:0001112	Leber optic atrophy
HP:0001138	Optic neuropathy
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy

GWAS associations

0 associations (top):

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
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
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
C536035	Maternally Inherited Leigh Syndrome (supp.)
C537475	Mitochondrial complex I deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2363065 (PROTEIN COMPLEX)

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

ChEMBL bioactivities

8 potent at pChembl≥5 of 18 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.06	IC50	870	nM	R-(+)-MARMIN-6’-UNDECANOATE
6.04	IC50	920	nM	R-(+)-MARMIN-6’-LINOLEATE
5.63	IC50	2350	nM	R-(+)-MARMIN-6’-LINOLEATE
5.51	IC50	3080	nM	R-(+)-MARMIN-6’-OCTANOATE
5.43	IC50	3670	nM	R-(+)-MARMIN-6’-UNDECANOATE
5.43	IC50	3710	nM	R-(+)-MARMIN-6’-OCTANOATE
5.31	IC50	4900	nM	(+)-9’-ISOVALEROXYLARICIRESINOL
5.04	IC50	9100	nM	(+)-9’-ISOVALEROXYLARICIRESINOL

PubChem BioAssay actives

8 with measured affinity, of 28 total; 4 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
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] undecanoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	0.8700	uM
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] (9Z,12Z)-octadeca-9,12-dienoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	0.9200	uM
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] octanoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	3.0800	uM
[(2S,3R,4R)-2-(4-hydroxy-3-methoxyphenyl)-4-[(4-hydroxy-3-methoxyphenyl)methyl]oxolan-3-yl]methyl 3-methylbutanoate	739269: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1,10-phenanthroline-induced HIF1 activation incubated for 30 mins prior to 1,10-phenanthroline-challenge measured after 16 hrs by luciferase reporter assay	ic50	4.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
enniatins	affects cotreatment, increases expression, decreases expression	5
beauvericin	increases expression, decreases expression, affects cotreatment	3
Air Pollutants	increases abundance, decreases expression	3
Valproic Acid	increases expression, affects methylation, decreases expression	3
bisphenol A	decreases reaction, increases abundance, decreases expression, increases expression	2
Atrazine	decreases expression	2
1-Methyl-4-phenylpyridinium	decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
ginger extract	increases abundance, increases expression, decreases reaction	1
methylparaben	decreases expression	1
sodium arsenite	increases mutagenesis	1
ochratoxin A	affects cotreatment, increases expression	1
2-chloroethyl ethyl sulfide	increases expression	1
tris(chloroethyl)phosphate	increases abundance, increases expression	1
1-methyl-4-phenyl-2,3-dihydropyridinium	decreases expression	1
licochalcone B	decreases expression	1
Acetaminophen	decreases expression	1
Cadmium	increases expression, increases abundance	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Dust	decreases expression, increases abundance	1
Flame Retardants	increases abundance, increases expression	1
Fluorides	decreases expression, decreases reaction, increases abundance	1
Indomethacin	affects cotreatment, increases expression	1
Oils, Volatile	decreases reaction, increases abundance, increases expression	1
Paraquat	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Rotenone	decreases expression	1
Silicon Dioxide	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2353025	Binding	Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation at 30 uM incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	Semisynthetic studies identify mitochondria poisons from botanical dietary supplements–geranyloxycoumarins from Aegle marmelos. — Bioorg Med Chem

Clinical trials (associated diseases)

311 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
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide
NCT01229735	PHASE4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures