NDUFA1

Summary

NDUFA1 (NADH:ubiquinone oxidoreductase subunit A1, HGNC:7683) is a protein-coding gene on chromosome Xq24, encoding NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 (O15239). Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. It is a selective cancer dependency (DepMap: 24.4% of cell lines).

The human NDUFA1 gene codes for an essential component of complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha-helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and might act as an anchor for the NADH:ubiquinone oxidoreductase complex at the inner mitochondrial membrane. However, the NDUFA1 peptide is one of about 31 components of the “hydrophobic protein” (HP) fraction of complex I which is involved in proton translocation. Thus the NDUFA1 peptide may also participate in that function.

Source: NCBI Gene 4694 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial complex I deficiency, nuclear type 12 (Definitive, GenCC) — +3 more curated relationships
• Clinical variants (ClinVar): 49 total — 1 pathogenic
• Phenotypes (HPO): 61
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 24.4% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004541

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7683
Approved symbol	NDUFA1
Name	NADH:ubiquinone oxidoreductase subunit A1
Location	Xq24
Locus type	gene with protein product
Status	Approved
Aliases	MWFE, CI-MWFE
Ensembl gene	ENSG00000125356
Ensembl biotype	protein_coding
OMIM	300078
Entrez	4694

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000371437, ENST00000851854, ENST00000927464

RefSeq mRNA: 1 — MANE Select: NM_004541 NM_004541

CCDS: CCDS14590

Canonical transcript exons

ENST00000371437 — 3 exons

Exon	Start	End
ENSE00000854502	119873304	119873393
ENSE00001455224	119876514	119876662
ENSE00001455228	119871832	119872013

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 121.9866 / max 1714.4589, expressed in 1828 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197407	119.9545	1828
197406	0.8228	476
197405	0.7657	344
209794	0.4436	228

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	99.78	gold quality
cardiac ventricle	UBERON:0002082	99.74	gold quality
heart left ventricle	UBERON:0002084	99.74	gold quality
heart right ventricle	UBERON:0002080	99.72	gold quality
apex of heart	UBERON:0002098	99.70	gold quality
right atrium auricular region	UBERON:0006631	99.69	gold quality
cardiac atrium	UBERON:0002081	99.68	gold quality
myocardium	UBERON:0002349	99.68	gold quality
heart	UBERON:0000948	99.63	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.57	gold quality
mucosa of transverse colon	UBERON:0004991	99.55	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.47	gold quality
renal medulla	UBERON:0000362	99.46	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.45	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.44	gold quality
prefrontal cortex	UBERON:0000451	99.43	gold quality
gastrocnemius	UBERON:0001388	99.42	gold quality
paraflocculus	UBERON:0005351	99.42	gold quality
adult mammalian kidney	UBERON:0000082	99.41	gold quality
nucleus accumbens	UBERON:0001882	99.41	gold quality
frontal pole	UBERON:0002795	99.41	gold quality
endometrium epithelium	UBERON:0004811	99.41	gold quality
caudate nucleus	UBERON:0001873	99.40	gold quality
middle frontal gyrus	UBERON:0002702	99.40	gold quality
diaphragm	UBERON:0001103	99.39	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.38	gold quality
adenohypophysis	UBERON:0002196	99.37	gold quality
metanephros cortex	UBERON:0010533	99.37	gold quality
right frontal lobe	UBERON:0002810	99.36	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.36	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-8410	yes	47.55
E-HCAD-10	yes	33.75
E-MTAB-10042	yes	10.09
E-MTAB-5061	no	598.52
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

10 targeting NDUFA1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-3187-3P	97.38	65.80	904

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 24.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 12)

• Species-specific and mutant MWFE proteins effect on the assembly of a functional mammalian mitochondrial complex I. (PMID:11937507)
• A family-based association study finds that the NDUFA1 gene is unlikely to harbor a major visual loss susceptibility locus for Leber hereditary optic neuropathy. (PMID:12084895)
• Oxidative stress and partial deficiencies of mitochondrial complex I are key factors in the pathogenesis of Parkinson’s disease. (REVIEW) (PMID:15038604)
• Suppression of NDUFA1 expression could represent a key pathogenic mechanism in the development of basal cell carcinoma (PMID:15854127)
• Two novel p.Gly8Arg and p.Arg37Ser hemizygous mutations in NDUFA1 were identified in two unrelated male patients presenting with Leigh’s syndrome and with myoclonic epilepsy and developmental delay. (PMID:17262856)
• hypothesize that the novel G32R mutation in NDUFA1 is causing complex I deficiency either by itself or in synergy with additional mtDNA variants (PMID:19185523)
• Mutations in the NDUFA1 gene is linked to a delayed mitochondrial network recovery in OXPHOS disorders. (PMID:20153825)
• Heterozygous mutation in the X chromosomal NDUFA1 gene in a girl with complex I deficiency (PMID:21596602)
• Fanconi anemia complementation group A mutants show defective respiration through Complex I, diminished ATP production and metabolic sufferance with an increased AMP/ATP ratio. (PMID:23791750)
• Results from a study on gene expression variability markers in early-stage human embryos shows that NDUF1A is a putative expression variability marker for the 3-day, 8-cell embryo stage. (PMID:26288249)
• The gene signature of OPA1, CTSA, NDUFA1, STK10 and PRDX1 was able to identify patients post-implant with a sensitivity of 91% and a specificity of 86% in discrimination between post-implant group and healthy controls. (PMID:27177495)
• NDUFA1 p.Gly32Arg variant in early-onset dementia. (PMID:35131137)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufa1	ENSDARG00000036329
mus_musculus	Ndufa1	ENSMUSG00000016427
rattus_norvegicus	Ndufa1	ENSRNOG00000071176
drosophila_melanogaster	ND-MWFE	FBGN0085468

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 — O15239 (reviewed: O15239)

Alternative names: Complex I-MWFE, NADH-ubiquinone oxidoreductase MWFE subunit

All UniProt accessions (2): O15239, Q6IBB5

UniProt curated annotations — full annotation on UniProt →

Function. Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone.

Subunit / interactions. Complex I is composed of 45 different subunits.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Primarily expressed in heart and skeletal muscle.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 12 (MC1DN12) [MIM:301020] 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 NDUFA1 subunit family.

RefSeq proteins (1): NP_004532* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR017384	NADH_Ub_cplx-1_asu_su-1	Family

Pfam: PF15879

UniProt features (6 total): sequence variant 4, chain 1, transmembrane region 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-O15239-F1	97.19	0.99

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-611105	Respiratory electron transport
R-HSA-6799198	Complex I biogenesis
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism

MSigDB gene sets: 338 (showing top): MODULE_93, MORF_MBD4, XU_GH1_AUTOCRINE_TARGETS_UP, MODULE_151, MODULE_77, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT, GCM_MYCL1, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, EVI1_05, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, MORF_SKP1A

GO Biological Process (4): mitochondrial electron transport, NADH to ubiquinone (GO:0006120), aerobic respiration (GO:0009060), 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), mitochondrial membrane (GO:0031966), respiratory chain complex I (GO:0045271), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Respiratory electron transport	1
Metabolism	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
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
mitochondrial envelope	1
organelle membrane	1
NADH dehydrogenase complex	1
respiratory chain complex	1
transmembrane transporter complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1420 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFA1	NDUFA2	O43678	900
NDUFA1	NDUFS6	O75380	894
NDUFA1	NDUFS4	O43181	875
NDUFA1	NDUFA11	Q86Y39	875
NDUFA1	NDUFV2	P19404	857
NDUFA1	NDUFS8	O00217	850
NDUFA1	MT-ND1	P03886	850
NDUFA1	NDUFS2	O75306	839
NDUFA1	NDUFA6	P56556	826
NDUFA1	NDUFS1	P28331	818
NDUFA1	NDUFV1	P49821	818
NDUFA1	NDUFS5	O43920	811
NDUFA1	COXFA4	O00483	808
NDUFA1	NDUFA10	O95299	806
NDUFA1	NDUFAF2	Q8N183	801

IntAct

20 interactions, top by confidence:

A	B	Type	Score
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
TOR1AIP2	TMEM223	psi-mi:“MI:0914”(association)	0.530
NDUFA8	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFA1	NDUFA7	psi-mi:“MI:0914”(association)	0.530
NDUFA7	NDUFA1	psi-mi:“MI:0914”(association)	0.530
NDUFA9	NDUFA1	psi-mi:“MI:0914”(association)	0.530
TRIM63	NDUFA1	psi-mi:“MI:0915”(physical association)	0.370
NDUFA1	SMURF2	psi-mi:“MI:0915”(physical association)	0.370
NDUFA6	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFB7	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFA1	NDUFS4	psi-mi:“MI:0914”(association)	0.350
NDUFV3	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFB11	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFA1	NDUFS8	psi-mi:“MI:0914”(association)	0.350
GOLGB1	NDUFA1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (50): NDUFA1 (Two-hybrid), NDUFA1 (Two-hybrid), NDUFA1 (Affinity Capture-MS), NDUFA1 (Affinity Capture-MS), NDUFA1 (Affinity Capture-MS), NDUFA1 (Affinity Capture-MS), NDUFV1 (Affinity Capture-MS), ND4 (Affinity Capture-MS), ND5 (Affinity Capture-MS), NDUFV2 (Affinity Capture-MS), NDUFS4 (Affinity Capture-MS), NDUFS6 (Affinity Capture-MS), NDUFV3 (Affinity Capture-MS), NDUFA12 (Affinity Capture-MS), NDUFA1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D8PDP8, A0A1D8PHA2, A3LWK1, A5E7J0, A6ZPQ9, A7TQM5, B3LQ47, B9WK46, C0HK62, C4R127, C4YBX9, C4YTL7, C7GR49, C8ZBF1, G2TRP5, O14949, O15239, O94705, P07255, P08525, P0CB71, P0CB72, P10174, P11950, P13271, P32799, P37299, P48305, P48503, P49346, P50523, Q06405, Q20779, Q2L897, Q3E7B2, Q54V76, Q5R597, Q6BL60, Q6CLM9, Q6FW43

Diamond homologs: O15239, O35683, Q02377, Q7JGX4, Q8SPF0, Q8SPS2, Q9WU08

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NDUFA1	“form complex”	“NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I”	binding
TFEB	“up-regulates quantity by expression”	NDUFA1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 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	10	118.2×	1e-18
Respiratory electron transport	10	68.0×	2e-16
Aerobic respiration and respiratory electron transport	10	63.2×	3e-16

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	9	215.1×	4e-19
proton motive force-driven mitochondrial ATP synthesis	10	175.5×	4e-20
aerobic respiration	10	165.2×	4e-20

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	10
Likely benign	6
Benign	11

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
11649	NM_004541.4(NDUFA1):c.111G>C (p.Arg37Ser)	Pathogenic

SpliceAI

391 predictions. Top by Δscore:

Variant	Effect	Δscore
X:119872010:CAAG:C	donor_loss	0.9900
X:119872011:AAG:A	donor_loss	0.9900
X:119872014:G:A	donor_loss	0.9900
X:119872015:T:A	donor_loss	0.9900
X:119871796:G:GG	donor_gain	0.9600
X:119871878:GAA:G	donor_gain	0.9600
X:119873389:CAAAG:C	donor_loss	0.9500
X:119873390:AAAG:A	donor_loss	0.9500
X:119873391:AAG:A	donor_loss	0.9500
X:119873392:AG:A	donor_loss	0.9500
X:119873393:GGTAA:G	donor_loss	0.9500
X:119873395:T:G	donor_loss	0.9500
X:119871878:G:GT	donor_gain	0.9400
X:119871881:G:GG	donor_gain	0.9400
X:119876512:AG:A	acceptor_gain	0.9400
X:119876513:GG:G	acceptor_gain	0.9400
X:119873300:GAAG:G	acceptor_loss	0.9200
X:119873302:A:AT	acceptor_loss	0.9200
X:119873396:AAGAT:A	donor_loss	0.9100
X:119871996:TTC:T	donor_gain	0.9000
X:119872014:G:GG	donor_gain	0.9000
X:119871861:C:A	donor_gain	0.8800
X:119872009:GCAAG:G	donor_gain	0.8800
X:119871880:A:AG	donor_gain	0.8600
X:119871872:G:GT	donor_gain	0.8200
X:119871841:G:T	donor_gain	0.8100
X:119873302:A:AG	acceptor_gain	0.8100
X:119873303:G:GG	acceptor_gain	0.8100
X:119873299:T:TA	acceptor_gain	0.8000
X:119875342:T:A	acceptor_gain	0.8000

AlphaMissense

455 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:119873351:A:C	R50S	0.979
X:119873351:A:T	R50S	0.979
X:119876518:T:C	L66S	0.968
X:119871915:T:A	W2R	0.966
X:119871915:T:C	W2R	0.966
X:119871954:T:C	C15R	0.962
X:119871976:C:A	A22D	0.962
X:119876514:G:C	G65R	0.962
X:119873312:G:C	R37S	0.948
X:119873312:G:T	R37S	0.948
X:119873350:G:C	R50T	0.948
X:119873350:G:T	R50I	0.944
X:119873353:A:T	D51V	0.936
X:119871918:T:C	F3L	0.935
X:119871920:C:A	F3L	0.935
X:119871920:C:G	F3L	0.935
X:119871943:T:A	V11D	0.931
X:119871928:T:A	L6H	0.928
X:119873353:A:C	D51A	0.928
X:119872013:G:C	K34N	0.927
X:119872013:G:T	K34N	0.927
X:119871948:G:C	G13R	0.925
X:119871967:C:A	P19Q	0.925
X:119873359:G:C	R53P	0.911
X:119873309:A:C	K36N	0.904
X:119873309:A:T	K36N	0.904
X:119871928:T:G	L6R	0.902
X:119871967:C:G	P19R	0.901
X:119873352:G:C	D51H	0.897
X:119871949:G:A	G13D	0.895

dbSNP variants (sampled 300 via entrez): RS1000036796 (X:119869971 C>T), RS1001126389 (X:119871222 T>C), RS1001711591 (X:119874306 A>G), RS1002084422 (X:119874144 T>G), RS1002497138 (X:119876911 C>T), RS1002715819 (X:119872182 C>T), RS1003164098 (X:119874754 A>C), RS1005065580 (X:119870035 C>G,T), RS1005147641 (X:119876878 CTTTA>C), RS1005828772 (X:119875882 C>G,T), RS1006724363 (X:119873115 T>C), RS1007623548 (X:119872238 T>C), RS1009482383 (X:119871204 C>G), RS1010761949 (X:119874291 A>C), RS1013032084 (X:119872146 G>A)

Disease associations

OMIM: gene MIM:300078 | disease phenotypes: MIM:301020

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 12	Definitive	X-linked
Leigh syndrome	Moderate	X-linked
mitochondrial complex I deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mitochondrial disease	Moderate	XL
Leigh syndrome	Moderate	XL

Mondo (3): mitochondrial complex I deficiency, nuclear type 12 (MONDO:0026720), Leigh syndrome (MONDO:0009723), mitochondrial complex I deficiency (MONDO:0100133)

Orphanet (0):

HPO phenotypes

61 total (30 of 61 shown, HPO-id order):

HPO	Term
HP:0000114	Proximal tubulopathy
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000408	Progressive sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000510	Rod-cone dystrophy
HP:0000543	Optic disc pallor
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000726	Dementia
HP:0000750	Delayed speech and language development
HP:0000817	Reduced eye contact
HP:0000819	Diabetes mellitus
HP:0001138	Optic neuropathy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001266	Choreoathetosis
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness
HP:0001336	Myoclonus
HP:0001419	X-linked recessive inheritance
HP:0001508	Failure to thrive

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

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
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

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	4
bisphenol A	affects expression, decreases expression	3
Acetaminophen	affects cotreatment, decreases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Doxorubicin	increases expression, affects response to substance	2
bisphenol F	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
kojic acid	increases expression	1
tris(2-butoxyethyl) phosphate	decreases expression, increases abundance	1
arsenite	affects binding, increases reaction	1
methylparaben	decreases expression	1
cobaltous chloride	decreases expression	1
ochratoxin A	increases expression	1
3-methyladenine	affects cotreatment, decreases expression, decreases reaction	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	decreases expression	1
acipimox	decreases expression	1
1-nitropyrene	increases expression, affects cotreatment, decreases expression, decreases reaction	1
chloropicrin	increases expression	1
K 7174	decreases expression	1
fenpyroximate	increases expression	1
pyrimidifen	increases expression	1
picoxystrobin	increases expression	1
Sunitinib	decreases expression	1
Vehicle Emissions	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	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)

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

Trial	Phase	Status	Title
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
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)
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells