MT-ND3

Summary

MT-ND3 (mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 3, HGNC:7458) is a protein-coding gene on chromosome mitochondria, encoding NADH-ubiquinone oxidoreductase chain 3 (P03897). 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. Located in mitochondrial inner membrane. Part of respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and Parkinson’s disease.

Source: NCBI Gene 4537 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +4 more curated relationships
• Clinical variants (ClinVar): 53 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 81
• Druggable target: yes

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7458
Approved symbol	MT-ND3
Name	mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 3
Location	mitochondria
Locus type	gene with protein product
Status	Approved
Aliases	ND3, NAD3
Ensembl gene	ENSG00000198840
Ensembl biotype	protein_coding
OMIM	516002
Entrez	4537

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000361227

RefSeq mRNA: 0 — MANE Select: None

Canonical transcript exons

ENST00000361227 — 1 exons

Exon	Start	End
ENSE00001435444	10059	10404

Expression profiles

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

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 301.5421 / max 45373.1920, expressed in 1823 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194915	277.6517	1823
194916	20.1539	1756
194912	1.9691	545
194917	1.7674	423

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.99	gold quality
adipose tissue	UBERON:0001013	99.99	gold quality
left lobe of thyroid gland	UBERON:0001120	99.99	gold quality
cortex of kidney	UBERON:0001225	99.99	gold quality
right adrenal gland	UBERON:0001233	99.99	gold quality
left adrenal gland	UBERON:0001234	99.99	gold quality
right uterine tube	UBERON:0001302	99.99	gold quality
left coronary artery	UBERON:0001626	99.99	gold quality
heart left ventricle	UBERON:0002084	99.99	gold quality
subcutaneous adipose tissue	UBERON:0002190	99.99	gold quality
prostate gland	UBERON:0002367	99.99	gold quality
mucosa of transverse colon	UBERON:0004991	99.99	gold quality
thoracic mammary gland	UBERON:0005200	99.99	gold quality
right atrium auricular region	UBERON:0006631	99.99	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	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
Brodmann (1909) area 9	UBERON:0013540	99.99	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.99	gold quality
left adrenal gland cortex	UBERON:0035825	99.99	gold quality
right adrenal gland cortex	UBERON:0035827	99.99	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.99	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.99	gold quality
pituitary gland	UBERON:0000007	99.98	gold quality
zone of skin	UBERON:0000014	99.98	gold quality
adult mammalian kidney	UBERON:0000082	99.98	gold quality
colonic epithelium	UBERON:0000397	99.98	gold quality
endocervix	UBERON:0000458	99.98	gold quality
heart	UBERON:0000948	99.98	gold quality

Single-cell (SCXA)

Detected in 73 experiment(s), a significant marker in 38.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	28368.37
E-HCAD-15	yes	23072.79
E-CURD-88	yes	20891.41
E-MTAB-10287	yes	18997.75
E-GEOD-139324	yes	18256.37
E-MTAB-8322	yes	17782.16
E-MTAB-6308	yes	17262.47
E-MTAB-11011	yes	16773.01
E-CURD-46	yes	16416.43
E-MTAB-8142	yes	15842.63
E-MTAB-6505	yes	15043.21
E-MTAB-7407	yes	14751.39
E-GEOD-124263	yes	14707.52
E-MTAB-9435	yes	14546.39
E-CURD-55	yes	14266.45

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): THRA

Literature-anchored findings (GeneRIF, showing 21)

• mitochondrial ND3 gene mutation may have a role in causing in Leigh syndrome with early lethality (PMID:14764913)
• This is the first description of infantile Leigh syndrome due to a maternally transmitted T10191C substitution in ND3 and not due to a de novo mutation. (PMID:16023078)
• These results show that the 10197G>A mutation in the mitochondrial ND3 gene should be considered as a common mtDNA mutation responsible for Leigh syndrome and dystonia. (PMID:17152068)
• study reports a novel heteroplasmic m.10197G>A mutation in the ND3 gene in three Korean children with bilateral basal ganglia lesions and partial deficiencies of respiratory chain complex I activity (PMID:17413873)
• These findings suggest that the clinical presentations associated with the mtND3*10197A (m.10197G>A) mutation (ND3) are much wider, encompassing those of LDYT and Leigh syndrome. (PMID:19458970)
• 2 cases with a MELAS-like phenotype with additional unique features of epilepsia partialis continua accompanied by evolving lesions of the rolandic & calcarine cortices; both carried mutations in the MT-ND3 gene – mt.10158T>C & mt.10191T>C (PMID:19520270)
• mutations in the ND3 and ND5 genes in patients showing clinical features of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (PMID:19617458)
• this short clinical review we evaluate the case reports of the m.10191T>C mutation causing complex I-deficient Leigh syndrome described in the literature. (PMID:22364517)
• Point mutations m.10191T>C in mitochondrial ND3 gene, m.13513G>A in ND5 gene and m.14,453G>A in ND6 gene were detected in three Chinese children with Leigh synrome dur to complex I deficiency. (PMID:22947169)
• Hypoxia, oxidative stress, and saturated fatty acids impacted mitochondrial-mediated cell apoptosis and had promotion on MT-ND3 expression in hepatocytes. (PMID:24020820)
• The 10398G allele and Haplogroup I appear to confer significant protective effects for Fuchs endothelial corneal dystrophy (PMID:24917144)
• 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)
• Earlier age at onset was noted in male Chinese Machado-Joseph disease patients with MT-ND3 gene 10398A polymorphism (PMID:26336829)
• In the current study, we first took clinical and molecular datasets from case-control studies to determine the association between the ND3 G10398A mutation and breast cancer. (PMID:26782384)
• genetic variants not associated with aggressive prostate cancer in overweight or obese Mexicans (PMID:27187822)
• Disruption of FASTKD1 increases ND3 mRNA level. Disruption of FASTKD4 reduces it. Very low levels of FASTKD4 are sufficient to prevent ND3 loss. (PMID:28335001)
• we did not find somatic mutations in the sequence of the ATP6 and/or ND3 genes in postmenopausal Mexican-Mestizo women with breast cancer (PMID:29414393)
• rs28358278, rs2853826, and rs41467651 polymorphisms of MTND3 increase the susceptibility to gastric cancer development. (PMID:30275759)
• Patient specific Induced Pluripotent Stem Cells with high mutational load (ND3high - iPSC) showed a distinct metabolite profile compared with ND3low - iPSC and control-iPSCs. Metabolites that contributed to this distinction were pyruvate, malic acid, palmitic acid, stearic acid, and lactic acid. (PMID:30721581)
• NGS-based mtDNA Profiling Could Reveal Genetic Alterations in Schizophrenia. (PMID:34060999)
• Lack of association between single polymorphic variants of the mitochondrial nicotinamide adenine dinucleotide dehydrogenase 3, and 4L (MT-ND3 and MT-ND4L) and male infertility. (PMID:34120353)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mt-nd3	ENSDARG00000063914
mus_musculus	mt-Nd3	ENSMUSG00000064360
rattus_norvegicus	Mt-nd3	ENSRNOG00000033615
drosophila_melanogaster	mt:ND3	FBGN0013681

Protein

Protein identifiers

NADH-ubiquinone oxidoreductase chain 3 — P03897 (reviewed: P03897)

Alternative names: NADH dehydrogenase subunit 3

All UniProt accessions (2): P03897, Q7GXZ5

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 of complex I.

Subunit / interactions. Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits. Interacts with TMEM186. Interacts with TMEM242.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry. Mitochondrial complex I deficiency, mitochondrial type 1 (MC1DM1) [MIM:500014] A form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the complex I subunit 3 family.

RefSeq proteins (0): (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000440	NADH_UbQ/plastoQ_OxRdtase_su3	Family
IPR038430	NDAH_ubi_oxred_su3_sf	Homologous_superfamily

Pfam: PF00507

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (11 total): sequence variant 7, transmembrane region 3, chain 1

Structure

Experimental structures (PDB)

5 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

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P03897-F1	91.73	0.67

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

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

MSigDB gene sets: 280 (showing top): GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, 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_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_CELLULAR_RESPONSE_TO_CORTICOSTEROID_STIMULUS, GOBP_ATP_BIOSYNTHETIC_PROCESS, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (8): mitochondrial electron transport, NADH to ubiquinone (GO:0006120), response to oxidative stress (GO:0006979), aerobic respiration (GO:0009060), response to light intensity (GO:0009642), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), cellular response to glucocorticoid stimulus (GO:0071385), response to hormone (GO:0009725), proton transmembrane transport (GO:1902600)

GO Molecular Function (2): NADH dehydrogenase (ubiquinone) activity (GO:0008137), protein binding (GO:0005515)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), respiratory chain complex I (GO:0045271), membrane (GO:0016020), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-3 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	2
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
response to stress	1
cellular respiration	1
response to light stimulus	1
oxidative phosphorylation	1
proton motive force-driven ATP synthesis	1
response to glucocorticoid	1
cellular response to corticosteroid stimulus	1
response to endogenous stimulus	1
response to chemical	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
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
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

2911 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MT-ND3	MT-ND6	P03923	999
MT-ND3	MT-ND1	P03886	999
MT-ND3	MT-ND4L	P03901	999
MT-ND3	MT-ND5	P03915	999
MT-ND3	MT-ND4	P03905	999
MT-ND3	MT-ND2	P03891	999
MT-ND3	MT-ATP6	P00846	974
MT-ND3	MT-ATP8	P03928	958
MT-ND3	MT-CYB	P00156	955
MT-ND3	NDUFS7	O75251	950
MT-ND3	MT-CO3	P00414	947
MT-ND3	MT-CO1	P00395	919
MT-ND3	MT-CO2	P00403	919
MT-ND3	PTGS1	P23219	884
MT-ND3	NDUFV1	P49821	879

IntAct

6 interactions, top by confidence:

A	B	Type	Score
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
APP	MT-ND3	psi-mi:“MI:0915”(physical association)	0.520
NDUFA6	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NRAS	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): ND3 (Affinity Capture-MS), ND3 (Affinity Capture-MS), ND3 (Co-fractionation), ND3 (Affinity Capture-MS), ND3 (Cross-Linking-MS (XL-MS)), ND3 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A8DQI7, A8DQK7, O03202, O21332, O21513, O21519, O21540, O21560, O21566, O21572, O21575, O21578, O21584, O21590, O21592, O21595, O21598, O21601, O21604, O21610, O21613, O78753, O79434, O79880, P03897, P03898, P03899, P38600, P48654, P48912, P68307, P68308, P92697, Q2I3F4, Q3L6Y6, Q5Y4Q3, Q8HQB1, Q8W9M9, Q8WAB4, Q94P36

Diamond homologs: A8DQI7, A8DQK7, O03171, O03202, O03252, O21332, O21513, O21519, O21540, O21543, O21546, O21549, O21554, O21560, O21563, O21566, O21569, O21572, O21575, O21578, O21581, O21584, O21587, O21590, O21592, O21595, O21598, O21601, O21604, O21607, O21610, O21613, O21616, O47874, O78686, O78753, O79102, O79408, O79434, O79880

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MT-ND3	“form complex”	“NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	20
Likely benign	10
Benign	11

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
4528936	NC_012920.1:m.8478_13589del	Pathogenic
9712	NC_012920.1(MT-ND3):m.10191T>C	Pathogenic
9714	NC_012920.1(MT-ND3):m.10158T>C	Pathogenic
9715	NC_012920.1(MT-ND3):m.10197G>A	Pathogenic
155887	NC_012920.1(MT-ND3):m.10254G>A	Likely pathogenic
4795901	NC_012920.1(MT-ND3):m.10125dup	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

725 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
M:10242:T:C	F62L	0.993
M:10244:C:A	F62L	0.993
M:10244:C:G	F62L	0.993
M:10221:T:C	F55L	0.990
M:10223:C:A	F55L	0.990
M:10223:C:G	F55L	0.990
M:10251:T:C	F65L	0.988
M:10253:T:A	F65L	0.988
M:10253:T:G	F65L	0.988
M:10179:T:C	F41L	0.987
M:10181:C:A	F41L	0.987
M:10181:C:G	F41L	0.987
M:10359:A:C	S101R	0.984
M:10255:A:T	D66V	0.978
M:10255:A:C	D66A	0.975
M:10209:T:C	F51L	0.974
M:10211:C:A	F51L	0.974
M:10211:C:G	F51L	0.974
M:10255:A:G	D66G	0.971
M:10397:A:C	W113C	0.970
M:10397:A:T	W113C	0.970
M:10224:T:C	F56L	0.968
M:10226:C:A	F56L	0.968
M:10226:C:G	F56L	0.968
M:10256:T:A	D66E	0.965
M:10256:T:G	D66E	0.965
M:10395:T:C	W113R	0.964
M:10173:T:C	C39R	0.957
M:10254:G:C	D66H	0.957
M:10258:T:C	L67P	0.957

dbSNP variants (sampled 300 via entrez): RS1057516062 (MT:8418 T>C), RS1057516063 (MT:9166 T>C), RS1057516064 (MT:9237 G>A), RS1057518824 (MT:8084 A>G,T), RS1057520074 (MT:10499 A>G), 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), RS1116905 (MT:8428 C>A,T), RS1116906 (MT:8460 A>G), RS1116907 (MT:8468 C>A,T), RS112133961 (MT:10127 A>G), RS118192098 (MT:8344 A>G)

Disease associations

OMIM: gene MIM:516002 | disease phenotypes: MIM:256000, MIM:540000, MIM:535000, MIM:500014, MIM:500001, MIM:251900

GenCC curated gene-disease

Disease	Classification	Inheritance
maternally-inherited Leigh syndrome	Supportive	Mitochondrial
mitochondrial complex I deficiency	Supportive	Autosomal recessive
Leber plus disease	Supportive	Mitochondrial

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	MT
Leigh syndrome	Definitive	MT

Mondo (11): mitochondrial disease (MONDO:0044970), Leigh syndrome (MONDO:0009723), MELAS syndrome (MONDO:0010789), hereditary optic neuropathy (MONDO:0020249), Leber hereditary optic neuropathy (MONDO:0010788), mitochondrial complex I deficiency, mitochondrial type 1 (MONDO:0027068), mitochondrial complex I deficiency (MONDO:0100133), Leber optic atrophy and dystonia (MONDO:0010772), mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy (MONDO:0020714), maternally-inherited Leigh syndrome (MONDO:0016814), Leber plus disease (MONDO:0020478)

Orphanet (7): Mitochondrial disease (Orphanet:68380), Leigh syndrome (Orphanet:506), MELAS (Orphanet:550), Hereditary optic neuropathy (Orphanet:98671), Leber hereditary optic neuropathy (Orphanet:104), Isolated complex I deficiency (Orphanet:2609), Leber plus disease (Orphanet:99718)

HPO phenotypes

81 total (30 of 81 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:0000543	Optic disc pallor
HP:0000580	Pigmentary retinopathy
HP:0000597	Ophthalmoparesis
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000816	Abnormality of Krebs cycle metabolism
HP:0000817	Reduced eye contact
HP:0000819	Diabetes mellitus
HP:0001138	Optic neuropathy
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001276	Hypertonia
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001399	Hepatic failure

GWAS associations

0 associations (top):

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
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
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
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
C536024	Marsden syndrome (supp.)
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)

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

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

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

Chemical	Actions (top 5)	PubMed papers
enniatins	affects cotreatment, increases expression, decreases expression	5
Air Pollutants	decreases expression, increases abundance	5
beauvericin	affects cotreatment, increases expression, decreases expression	3
Particulate Matter	decreases expression, increases abundance	3
bisphenol A	decreases expression	2
Atrazine	decreases expression	2
Plant Extracts	affects cotreatment, increases expression	2
1-Methyl-4-phenylpyridinium	decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	decreases expression	1
methylmercuric chloride	increases expression	1
methylparaben	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
ochratoxin A	affects cotreatment, increases expression	1
aflatoxin G1	affects cotreatment, increases expression	1
ferrous chloride	decreases expression	1
aflatoxin B2	affects cotreatment, increases expression	1
aflatoxin G2	increases expression, affects cotreatment	1
phenanthrene	decreases expression	1
perfluorodecanoic acid	decreases expression	1
fialuridine	decreases expression	1
1-methyl-4-phenyl-2,3-dihydropyridinium	decreases expression	1
monomethylpropion	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
K 7174	decreases expression	1
licochalcone B	decreases expression	1
Acetaminophen	decreases expression	1
Cadmium	increases abundance, increases 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

Cellosaurus cell lines

2 cell lines: 1 finite cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C6UK	SBG4	Finite cell line
CVCL_C6UL	SBG4-iPSC	Induced pluripotent stem cell

Clinical trials (associated diseases)

112 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
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
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
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)
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
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
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).