MT-ND6

Summary

MT-ND6 (mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 6, HGNC:7462) is a protein-coding gene on chromosome mitochondria, encoding NADH-ubiquinone oxidoreductase chain 6 (P03923). 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. Implicated in Leber hereditary optic neuropathy; Leigh disease; and spinal muscular atrophy with lower extremity predominant 2B.

Source: NCBI Gene 4541 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +5 more curated relationships
• Clinical variants (ClinVar): 117 total — 5 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 158
• Druggable target: yes

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7462
Approved symbol	MT-ND6
Name	mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 6
Location	mitochondria
Locus type	gene with protein product
Status	Approved
Aliases	NAD6, ND6
Ensembl gene	ENSG00000198695
Ensembl biotype	protein_coding
OMIM	516006
Entrez	4541

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000361681

RefSeq mRNA: 0 — MANE Select: None

Canonical transcript exons

ENST00000361681 — 1 exons

Exon	Start	End
ENSE00001434974	14149	14673

Expression profiles

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

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 149.8510 / max 48249.7221, expressed in 1813 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195269	42.5958	1736
195268	35.6102	1739
195270	25.7868	1722
195271	23.3463	1739
195272	10.6892	1474
195276	2.5543	620
195275	2.0140	461
195267	1.9462	601
195279	1.6097	607
195266	1.3518	311

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	99.99	gold quality
left uterine tube	UBERON:0001303	99.99	gold quality
right uterine tube	UBERON:0001302	99.98	gold quality
granulocyte	CL:0000094	99.97	gold quality
fundus of stomach	UBERON:0001160	99.97	gold quality
temporal lobe	UBERON:0001871	99.97	gold quality
caudate nucleus	UBERON:0001873	99.97	gold quality
putamen	UBERON:0001874	99.97	gold quality
amygdala	UBERON:0001876	99.97	gold quality
nucleus accumbens	UBERON:0001882	99.97	gold quality
hypothalamus	UBERON:0001898	99.97	gold quality
Ammon’s horn	UBERON:0001954	99.97	gold quality
apex of heart	UBERON:0002098	99.97	gold quality
right frontal lobe	UBERON:0002810	99.97	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.97	gold quality
right atrium auricular region	UBERON:0006631	99.97	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.97	gold quality
zone of skin	UBERON:0000014	99.96	gold quality
adult mammalian kidney	UBERON:0000082	99.96	gold quality
transverse colon	UBERON:0001157	99.96	gold quality
body of stomach	UBERON:0001161	99.96	gold quality
right adrenal gland	UBERON:0001233	99.96	gold quality
endometrium	UBERON:0001295	99.96	gold quality
gastrocnemius	UBERON:0001388	99.96	gold quality
skin of abdomen	UBERON:0001416	99.96	gold quality
skin of leg	UBERON:0001511	99.96	gold quality
right coronary artery	UBERON:0001625	99.96	gold quality
cerebellum	UBERON:0002037	99.96	gold quality
substantia nigra	UBERON:0002038	99.96	gold quality
heart left ventricle	UBERON:0002084	99.96	gold quality

Single-cell (SCXA)

Detected in 19 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	20463.46
E-CURD-112	yes	4260.61
E-GEOD-75367	yes	2839.53
E-MTAB-7381	yes	2419.92
E-MTAB-8205	yes	1736.92
E-MTAB-8495	yes	743.82
E-MTAB-10596	yes	601.10
E-CURD-122	yes	22.84
E-ENAD-27	no	2138.53
E-CURD-85	no	1909.02
E-MTAB-8911	no	1808.85
E-MTAB-8060	no	1549.32
E-CURD-88	no	1482.34
E-MTAB-6379	no	1460.80
E-CURD-55	no	1047.56

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 32)

• novel mitochondrial DNA nucleotide transversion, C14482A (M64I) was found to cause Leber’s hereditary optic neuropathy with visual recovery (PMID:12112086)
• mitochondrial ND6 may have a role in Leber’s hereditary optic neuropathy (PMID:15922297)
• Free radicals-mediated damage was studied in transmitochondrial cells harboring T14487C mutation in the ND6 gene of mtDNA. (PMID:16337195)
• Therefore, the coexistence of the A1555G mutation and T14484C mutations in this Chinese family indicate that the A1555G mutation may play a synergistic role in the phenotypic manifestation of LHON associated ND6 T14484C mutation. (PMID:17452034)
• T14484C and T14502C in ND6 gene are associated with Leber’s hereditary optic neuropathy in a Chinese family. (PMID:18440284)
• G10680A mutation of ND4 may play a synergistic role with the primary mutation T14484C of ND6, leading to the complete penetrance of Leber’s hereditary optic neuropathy in the presenting family. (PMID:19394449)
• Molecular analysis has led to identification of the known T14502C mutation in ND6 gene in Chinese families with Leber’s hereditary optic neuropathy. (PMID:19732751)
• missense mutation 14487T>C resulted in severe encephalopathies ranging from infantile Leigh syndrome to adult-onset progressive myoclonic epilepsy with dystonia in a five-generation family (PMID:20019223)
• the G14459A mutation is a candidate mutation for maternally inherited dystonia (PMID:20052369)
• These data suggested that the ND6 T14502C variant may modulate the phenotypic manifestation of the G11778A mutation in these Chinese pedigrees. (PMID:20691156)
• These results suggest that a different set of LHON-causing mutations is present in the South Indian population than in the European population (PMID:20809775)
• Liver MT-ND6 transcriptional activity and protein expression were decreased in nonalcoholic steatohepatitis, suggesting that the expression of this mitochondrial gene may play an important role in the disease progression. (PMID:22879518)
• 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)
• This study shows that m.14484T>C arose independently in a different mtDNA haplogroup and ethnic background in India, which may influence the clinical expression of the disease. (PMID:23674761)
• Protein modeling revealed loss of function mutations of ND6 and COX-II proteins in malignant vs benign tumors (PMID:24061460)
• The molecular diagnostics by the whole exome sequencing showed a novel de novo (c.1374-2A>C) mutation in the KRT10 gene responsible for the development of IWC (KRT10 defect was confirmed by immunofluorescent study). Concurrently, the m.14484T>C mutation in mitochondrial MTND6 gene (characteristic for Leber’s hereditary optic neuropathy or LHON) was detected in patient, his mother and brother (PMID:28944608)
• This review focuses on the role of mitochondrial genes in causing LHON and therapeutics available for treating the disease. A systematic search has been adopted in various databases using the keywords “LHON,” “mitochondria,” “ND1,” “ND4,” “ND6,” and “therapy” and the following review on mitochondrial genetics (PMID:29133631)
• In this study, 27.5% mutation was detected in North Indian LHON families. These results suggest that m.G11778A mutation is more frequent in this population. The results of the present study are compatible with studies of an Asian population and Northern European population. (PMID:29133642)
• Study identify a significant down-expression of MT-ND6 in men with Klinefelter syndrome. (PMID:29333085)
• Our study suggests to include haplogroup T as a possible genetic background influencing LHON penetrance and to consider the increase of mtDNA copy number as a protective factor from vision loss regardless the hetero/homoplasmic status of LHON primary mutations. (PMID:29774306)
• Analysis of variants in mitochondrial genome and their putative pathogenicity in tuberculosis patients from Mizoram, North east India. (PMID:32652230)
• Long-term screening for primary mitochondrial DNA variants associated with Leber hereditary optic neuropathy: incidence, penetrance and clinical features. (PMID:32861874)
• Circulating nicotinamide adenine dinucleotide-ubiquinone oxidoreductase chain 6 is associated with disease activity of anti-neutrophil cytoplasmic antibody-associated vasculitis. (PMID:33058842)
• Impact of Mitochondrial Genetic Variants in ND1, ND2, ND5, and ND6 Genes on Sperm Motility and Intracytoplasmic Sperm Injection (ICSI) Outcomes. (PMID:33475980)
• Mild Leber hereditary optic neuropathy (LHON) in a Western European family due to the rare Asian m.14502T>C variant in the MT-ND6 gene. (PMID:33858285)
• Circulating mitochondrial N-formyl peptides contribute to secondary nosocomial infection in patients with septic shock. (PMID:33888581)
• Hypermethylation of Hepatic Mitochondrial ND6 Provokes Systemic Insulin Resistance. (PMID:34141522)
• Leber’s hereditary optic neuropathy-associated ND6 14484T > C mutation caused pleiotropic effects on the complex I, RNA homeostasis, apoptosis and mitophagy. (PMID:35567411)
• Optimized allotopic expression of mitochondrial ND6 transgene restored complex I and apoptosis deficiencies caused by LHON-linked ND6 14484T > C mutation. (PMID:37537557)
• Maternally inherited non-syndromic hearing loss is linked with a novel mitochondrial ND6 gene mutation. (PMID:37561388)
• Reduced mitochondrial-encoded NADH dehydrogenase 6 gene expression drives inflammatory CD4[+]T cells in patients with systemic lupus erythematosus. (PMID:38242247)
• Evolutionary characteristics of the mitochondrial NADH dehydrogenase subunit 6 gene in some populations of four sympatric Mustela species (Mustelidae, Mammalia) from central Europe. (PMID:38664260)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mt-nd6	ENSDARG00000063922
mus_musculus	mt-Nd6	ENSMUSG00000064368
rattus_norvegicus	Mt-nd6	ENSRNOG00000029042

Protein

Protein identifiers

NADH-ubiquinone oxidoreductase chain 6 — P03923 (reviewed: P03923)

Alternative names: NADH dehydrogenase subunit 6

All UniProt accessions (2): P03923, U5Z977

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.

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. Leber hereditary optic neuropathy with dystonia (LDYT) [MIM:500001] A 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. LDYT is characterized by the association of optic atrophy and central vision loss with dystonia. The disease is caused by variants affecting the gene represented in this entry. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome (MELAS) [MIM:540000] Genetically heterogeneous disorder, characterized by episodic vomiting, seizures, and recurrent cerebral insults resembling strokes and causing hemiparesis, hemianopsia, or cortical blindness. The disease is caused by 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. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the complex I subunit 6 family.

RefSeq proteins (0): (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001457	NADH_UbQ/plastoQ_OxRdtase_su6	Family
IPR050269	ComplexI_Subunit6	Family

Pfam: PF00499

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (23 total): sequence variant 13, transmembrane region 6, sequence conflict 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-P03923-F1	84.61	0.51

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: 405 (showing top): GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, 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_ATP_BIOSYNTHETIC_PROCESS, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ELECTRON_TRANSPORT_CHAIN, GOCC_MITOCHONDRIAL_ENVELOPE

GO Biological Process (5): 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), proton transmembrane transport (GO:1902600)

GO Molecular Function (1): NADH dehydrogenase (ubiquinone) activity (GO:0008137)

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-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
mitochondrion	2
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
oxidative phosphorylation	1
proton motive force-driven ATP synthesis	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
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

1172 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MT-ND6	MT-ND2	P03891	999
MT-ND6	MT-ND3	P03897	999
MT-ND6	MT-ND4L	P03901	999
MT-ND6	MT-ND4	P03905	999
MT-ND6	MT-ND5	P03915	999
MT-ND6	MT-ND1	P03886	997
MT-ND6	MT-ATP6	P00846	974
MT-ND6	MT-CO3	P00414	966
MT-ND6	MT-CO1	P00395	963
MT-ND6	MT-CYB	P00156	959
MT-ND6	MT-CO2	P00403	945
MT-ND6	MT-ATP8	P03928	923
MT-ND6	NDUFS7	O75251	911
MT-ND6	NDUFV1	P49821	887
MT-ND6	PTGS1	P23219	881

IntAct

8 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
NDUFS3	NDUFB6	psi-mi:“MI:0914”(association)	0.640
NDUFS5	NDUFS8	psi-mi:“MI:0914”(association)	0.530
MT-ND6	SHANK3	psi-mi:“MI:0915”(physical association)	0.370
ACAD9	NDUFS2	psi-mi:“MI:0914”(association)	0.350
NDUFAF3	NDUFS8	psi-mi:“MI:0914”(association)	0.350
CLEC4A	RBFOX3	psi-mi:“MI:0914”(association)	0.350

BioGRID (28): ND6 (Affinity Capture-MS), ND6 (Affinity Capture-MS), ND6 (Affinity Capture-MS), ND6 (Affinity Capture-MS), ND6 (Two-hybrid), ND6 (Affinity Capture-MS), NDUFA10 (Co-fractionation), NDUFA12 (Co-fractionation), NDUFA13 (Co-fractionation), NDUFA6 (Co-fractionation), NDUFA9 (Co-fractionation), NDUFB10 (Co-fractionation), NDUFB3 (Co-fractionation), NDUFB4 (Co-fractionation), NDUFB5 (Co-fractionation)

ESM2 similar proteins: O03175, O03206, O21336, O78689, O78757, O79412, O79438, O79882, P03923, P03924, P03925, P03926, P24980, P34196, P38603, P41300, P41315, P43202, P48657, P48926, P92486, P92670, P92700, Q00543, Q1HK79, Q2I3G3, Q34573, Q36460, Q38PR1, Q4JQH6, Q5ULB0, Q71PB7, Q7Y8D2, Q8LX23, Q8W9G2, Q8W9M5, Q94VK5, Q953I3, Q95710, Q96070

Diamond homologs: O03175, O03206, O21336, O21407, O78689, O78757, O79412, O79438, O79557, O79679, O79882, P03923, P03924, P03925, P03926, P03927, P12777, P15553, P18941, P24980, P24981, P24982, P34196, P38603, P41300, P41315, P41322, P43189, P43190, P43191, P43192, P43193, P43194, P43195, P43196, P43197, P43198, P43199, P43200, P43201

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MT-ND6	“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 10 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.

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial respiratory chain complex I assembly	6	246.6×	2e-12
mitochondrial electron transport, NADH to ubiquinone	5	179.3×	9e-10
proton motive force-driven mitochondrial ATP synthesis	5	131.7×	3e-09
aerobic respiration	5	123.9×	3e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	9
Uncertain significance	41
Likely benign	23
Benign	32

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
224776	NC_012920.1:m.14248dupC	Pathogenic
430684	NC_012920.1(MT-TS2):m.10106_15067del	Pathogenic
430686	NC_012920.1(MT-TS2):m.12114_14420del	Pathogenic
9688	NC_012920.1(MT-ND6):m.14484T>C	Pathogenic
9694	NC_012920.1(MT-ND6):m.14487T>C	Pathogenic
209173	NC_012920.1(MT-ND6):m.14597A>G	Likely pathogenic
4795907	NC_012920.1(MT-ND6):m.14430A>G	Likely pathogenic
65513	NC_012920.1(MT-ND6):m.14482C>G	Likely pathogenic
65515	NC_012920.1(MT-ND6):m.14568C>T	Likely pathogenic
693726	NC_012920.1(MT-ND6):m.14465G>A	Likely pathogenic
800503	NC_012920.1(MT-ND6):m.14513_14514del	Likely pathogenic
9691	NC_012920.1(MT-ND6):m.14495A>G	Likely pathogenic
9692	NC_012920.1(MT-ND6):m.14453G>A	Likely pathogenic
9693	NC_012920.1(MT-ND6):m.14482C>A	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1083 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
M:14202:A:G	W158R	0.996
M:14473:A:C	F67L	0.995
M:14473:A:T	F67L	0.995
M:14475:A:G	F67L	0.995
M:14571:T:G	S35R	0.995
M:14568:C:G	G36R	0.992
M:14187:C:G	G163R	0.991
M:14460:C:G	A72P	0.991
M:14204:C:T	G157D	0.990
M:14493:C:G	G61R	0.990
M:14649:T:G	S9R	0.990
M:14492:C:T	G61E	0.989
M:14567:C:T	G36D	0.989
M:14223:A:G	W151R	0.988
M:14205:C:G	G157R	0.987
M:14556:A:G	C40R	0.987
M:14454:C:G	A74P	0.986
M:14559:C:G	G39R	0.986
M:14631:C:G	G15R	0.986
M:14589:C:G	G29R	0.985
M:14471:C:T	G68E	0.983
M:14490:C:G	G62R	0.983
M:14485:C:A	M63I	0.982
M:14485:C:G	M63I	0.982
M:14591:C:T	G28E	0.982
M:14520:C:G	G52R	0.980
M:14579:A:G	L32S	0.980
M:14459:G:T	A72E	0.979
M:14558:C:T	G39E	0.979
M:14493:C:A	G61W	0.978

dbSNP variants (sampled 300 via entrez): RS1057516069 (MT:14563 C>T), RS1057516070 (MT:14706 A>G), RS1057516071 (MT:14854 C>T), RS1057516072 (MT:15060 G>A), RS1057516073 (MT:15096 T>C), RS1057516074 (MT:15127 C>T), RS1057516075 (MT:15246 G>A), RS1057518823 (MT:15446 C>T), RS1057518882 (MT:14598 T>C), RS1057520097 (MT:15262 T>C), RS1057520103 (MT:14476 G>A,T), RS1057520206 (MT:15848 A>G), RS117017250 (MT:16360 C>T), RS117565943 (MT:16051 A>G), RS118203890 (MT:15950 G>A)

Disease associations

OMIM: gene MIM:516006 | disease phenotypes: MIM:535000, MIM:256000, MIM:540000, MIM:500001, MIM:605909

GenCC curated gene-disease

Disease	Classification	Inheritance
Leber hereditary optic neuropathy	Strong	Mitochondrial
maternally-inherited Leigh syndrome	Supportive	Mitochondrial
MELAS syndrome	Supportive	Mitochondrial
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 (17): Leber hereditary optic neuropathy (MONDO:0010788), dystonic disorder (MONDO:0003441), Leigh syndrome (MONDO:0009723), mitochondrial disease (MONDO:0044970), acute megakaryoblastic leukemia (MONDO:0018872), mediastinal germ cell tumor (MONDO:0021067), oncocytic adenoma (MONDO:0003424), blindness (disorder) (MONDO:0001941), parkinsonian disorder (MONDO:0021095), hereditary ataxia (MONDO:0100309), MELAS syndrome (MONDO:0010789), optic atrophy (MONDO:0003608), Leber optic atrophy and dystonia (MONDO:0010772), inherited retinal dystrophy (MONDO:0019118), autosomal recessive early-onset Parkinson disease 6 (MONDO:0011613)

Orphanet (9): Leber hereditary optic neuropathy (Orphanet:104), Leigh syndrome (Orphanet:506), Mitochondrial disease (Orphanet:68380), Acute megakaryoblastic leukemia (Orphanet:518), Hereditary ataxia (Orphanet:183518), MELAS (Orphanet:550), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Leber plus disease (Orphanet:99718), Young-onset Parkinson disease (Orphanet:2828)

HPO phenotypes

158 total (30 of 158 shown, HPO-id order):

HPO	Term
HP:0000044	Hypogonadotropic hypogonadism
HP:0000091	Abnormal renal tubule morphology
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:0000510	Rod-cone dystrophy
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:0000597	Ophthalmoparesis
HP:0000602	Ophthalmoplegia
HP:0000603	Central scotoma
HP:0000622	Blurred vision
HP:0000639	Nystagmus
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

GWAS associations

0 associations (top):

MeSH disease descriptors (13)

Descriptor	Name	Tree numbers
D001766	Blindness	C10.597.751.941.162; C11.966.075; C23.888.592.763.941.162
D020821	Dystonic Disorders	C10.228.662.300
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
D007947	Leukemia, Megakaryoblastic, Acute	C04.557.337.539.275.450; C15.378.508.539.275.450
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
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
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
D020734	Parkinsonian Disorders	C10.228.140.079.862; C10.228.662.600
D058499	Retinal Dystrophies	C11.768.585.658
C531684	Hereditary spinal ataxia (supp.)
C536024	Marsden syndrome (supp.)
C536035	Maternally Inherited Leigh Syndrome (supp.)
C565276	Parkinson Disease 6, Autosomal Recessive Early-Onset (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

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

Chemical	Actions (top 5)	PubMed papers
1-Methyl-4-phenylpyridinium	decreases expression, increases expression, decreases reaction	4
enniatins	increases expression, affects cotreatment, decreases expression	3
Air Pollutants	decreases expression, increases abundance	3
bisphenol A	affects cotreatment, increases expression, decreases expression	2
sodium arsenite	decreases expression	2
Atrazine	decreases expression	2
Doxorubicin	affects expression, decreases response to substance	2
Rotenone	decreases response to substance, decreases expression	2
Silicon Dioxide	increases expression, decreases expression	2
Tunicamycin	increases expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
geldanamycin	increases expression	1
beauvericin	affects cotreatment, decreases expression, increases expression	1
methylmercuric chloride	decreases expression	1
titanium dioxide	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
ochratoxin A	affects cotreatment, decreases expression, increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
acipimox	decreases expression	1
perfluorodecanoic acid	increases expression	1
1-methyl-4-phenyl-2,3-dihydropyridinium	decreases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
brequinar	decreases expression	1
azoxystrobin	decreases expression	1
deguelin	decreases expression	1
K 7174	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
pyrimidifen	decreases expression	1
thifluzamide	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

Cellosaurus cell lines

6 cell lines: 6 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C880	LHON1-hiPSC1	Induced pluripotent stem cell	Male
CVCL_C881	LHON1-hiPSC2	Induced pluripotent stem cell	Male
CVCL_C882	LHON1-hiPSC4	Induced pluripotent stem cell	Male
CVCL_C883	LHON1-hiPSC5	Induced pluripotent stem cell	Male
CVCL_D6I4	FINCBi005-A	Induced pluripotent stem cell	Male
CVCL_D6I5	FINCBi006-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01831934	PHASE4	COMPLETED	Responses to Influenza Vaccine in Patients With Mitochondrial Disorders (MELAS)
NCT00142259	PHASE4	UNKNOWN	Efficacy and Safety of DBS of the GPi in Patients With Primary Generalized and Segmental Dystonia
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT00998660	PHASE4	COMPLETED	RECHARGE Sub-Study to the Implantable Systems Performance Registry (ISPR)
NCT02263417	PHASE4	COMPLETED	A Randomized Controlled Trail Comparing Subthalamic and Pallidal Deep Brain Stimulation for Dystonia
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
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
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT00169403	PHASE3	UNKNOWN	Pallidal Stimulation in Patients With Idiopathic Generalised Dystonia
NCT03232320	PHASE3	COMPLETED	Meditoxin® Treatment in Patients With Cervical Dystonia
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)
NCT02176733	PHASE2	UNKNOWN	Trial of Cyclosporine in the Acute Phase of Leber Hereditary Optic Neuropathy
NCT00068913	PHASE2	UNKNOWN	Evaluating the Effectiveness of a Dichloroacetate in MELAS Syndrome
NCT00887562	PHASE2	COMPLETED	Study of Idebenone in the Treatment of Mitochondrial Encephalopathy Lactic Acidosis & Stroke-like Episodes
NCT01603446	PHASE2	COMPLETED	L-arginine Therapy on Endothelium-dependent Vasodilation & Mitochondrial Metabolism in MELAS Syndrome
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04475549	PHASE2	TERMINATED	Phase 2a Study of IW-6463 in Adults Diagnosed With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS)
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT06644534	PHASE2	RECRUITING	A Study to Assess TTI-0102 vs Placebo in MELAS Patients
NCT00001784	PHASE2	COMPLETED	Mexiletine for the Treatment of Focal Dystonia
NCT00105430	PHASE2	COMPLETED	Deep Brain Stimulation for Cervical Dystonia
NCT00106782	PHASE2	COMPLETED	Transcranial Electrical Polarization to Treat Focal Hand Dystonia
NCT00122044	PHASE2	COMPLETED	Childhood Hypertonia of Central Origin: A Trial of Anticholinergic Treatment Effects
NCT00169338	PHASE2	COMPLETED	Pallidal Stimulation in Patients With Post-anoxic and Idiopathic Dystonia
NCT00331669	PHASE2	UNKNOWN	Efficacy and Safety of Deep Brain Stimulation (DBS) of the Pallidal (GPi) in Patients With Tardive Dystonia
NCT02107261	PHASE2	COMPLETED	Incobotulinum Toxin A (Xeomin®) As A Treatment For Focal Task-Specific Dystonia Of The Musician’s Hand
NCT02470325	PHASE2	UNKNOWN	The Effects of Cannabis on Dystonia and Spasticity on Pediatric Patients
NCT05027997	PHASE2	COMPLETED	Exploratory Study of Dipraglurant (ADX48621) for the Treatment of Patients With Blepharospasm
NCT06412653	PHASE2	COMPLETED	Prospective Pilot Trial to Address Feasibility and Safety of Oral Zinc in GNAO1 Associated Disorders
NCT07304089	PHASE2	RECRUITING	A Study to Evaluate the Efficacy, Safety, and Tolerability of VIM0423 in Individuals With Isolated Dystonia
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)