NDUFA8

Summary

NDUFA8 (NADH:ubiquinone oxidoreductase subunit A8, HGNC:7692) is a protein-coding gene on chromosome 9q33.2, encoding NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8 (P51970). 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: 45.0% of cell lines).

The protein encoded by this gene belongs to the complex I 19 kDa subunit family. Mammalian complex I is composed of 45 different subunits. This protein has NADH dehydrogenase activity and oxidoreductase activity. It plays an important role in transfering electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 4702 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Moderate, ClinGen) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 42 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 33
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 45.0% of screened cell lines
• MANE Select transcript: NM_014222

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7692
Approved symbol	NDUFA8
Name	NADH:ubiquinone oxidoreductase subunit A8
Location	9q33.2
Locus type	gene with protein product
Status	Approved
Aliases	PGIV, MGC793
Ensembl gene	ENSG00000119421
Ensembl biotype	protein_coding
OMIM	603359
Entrez	4702

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000373768, ENST00000886470, ENST00000886471, ENST00000942086

RefSeq mRNA: 1 — MANE Select: NM_014222 NM_014222

CCDS: CCDS6835

Canonical transcript exons

ENST00000373768 — 4 exons

Exon	Start	End
ENSE00000927029	122148112	122148277
ENSE00000927030	122152245	122152408
ENSE00001461504	122144058	122144378
ENSE00001461511	122159627	122159779

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 99.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.6764 / max 215.3042, expressed in 1821 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
102379	39.1116	1820
102378	1.5648	876

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.25	gold quality
heart left ventricle	UBERON:0002084	98.89	gold quality
cardiac ventricle	UBERON:0002082	98.83	gold quality
right atrium auricular region	UBERON:0006631	98.82	gold quality
cardiac atrium	UBERON:0002081	98.65	gold quality
heart right ventricle	UBERON:0002080	98.50	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.23	gold quality
heart	UBERON:0000948	98.10	gold quality
caudate nucleus	UBERON:0001873	98.06	gold quality
anterior cingulate cortex	UBERON:0009835	98.03	gold quality
myocardium	UBERON:0002349	98.02	gold quality
cingulate cortex	UBERON:0003027	98.00	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.90	gold quality
left ventricle myocardium	UBERON:0006566	97.90	gold quality
triceps brachii	UBERON:0001509	97.88	gold quality
prefrontal cortex	UBERON:0000451	97.84	gold quality
right frontal lobe	UBERON:0002810	97.76	gold quality
biceps brachii	UBERON:0001507	97.66	gold quality
nucleus accumbens	UBERON:0001882	97.66	gold quality
middle temporal gyrus	UBERON:0002771	97.66	gold quality
gastrocnemius	UBERON:0001388	97.65	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.63	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.60	gold quality
putamen	UBERON:0001874	97.58	gold quality
mucosa of transverse colon	UBERON:0004991	97.49	gold quality
muscle of leg	UBERON:0001383	97.42	gold quality
left testis	UBERON:0004533	97.41	gold quality
right testis	UBERON:0004534	97.35	gold quality
rectum	UBERON:0001052	97.34	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.33	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting NDUFA8, 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-590-3P	99.96	74.34	6478
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-2053	99.57	69.15	1635
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-4480	99.42	66.02	735
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-522-3P	98.91	68.56	1817
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-603	98.58	68.28	1603
HSA-MIR-4303	98.01	68.13	2304
HSA-MIR-3691-3P	97.90	65.97	791
HSA-MIR-4288	97.11	67.23	1636

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 45.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 6)

• Intra-molecular disulfide bridges and the inter-membrane space localization of three Cx(9)C-containing subunits in human: NDUFS5, NDUFB7 and NDUFA8, are proposed. (PMID:21310150)
• This subunit of complex I is localized in the mitochondrial inter-membrane space. The protein contains intra-molecular disulfide bridges in the twin Cx(9)C motif. (PMID:21310150)
• A homozygous variant in NDUFA8 is associated with developmental delay, microcephaly, and epilepsy due to mitochondrial complex I deficiency. (PMID:32385911)
• Biallelic mutations in NDUFA8 cause complex I deficiency in two siblings with favorable clinical evolution. (PMID:33153867)
• Identification of Metabolic Syndrome-Related miRNA-mRNA Regulatory Networks and Key Genes Based on Bioinformatics Analysis. (PMID:35877019)
• NDUFA8 is transcriptionally regulated by EP300/H3K27ac and promotes mitochondrial respiration to support proliferation and inhibit apoptosis in cervical cancer. (PMID:38096616)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufa8	ENSDARG00000058041
mus_musculus	Ndufa8	ENSMUSG00000026895
rattus_norvegicus	Ndufa8	ENSRNOG00000005668
drosophila_melanogaster	ND-19	FBGN0035046
caenorhabditis_elegans		WBGENE00021849

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8 — P51970 (reviewed: P51970)

Alternative names: Complex I-19kD, Complex I-PGIV, NADH-ubiquinone oxidoreductase 19 kDa subunit

All UniProt accessions (1): P51970

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. Mitochondrion intermembrane space. Mitochondrion.

Post-translational modifications. May contain intrachain disulfide bonds, as evidenced by its electrophoretic mobility under reducing vs non-reducing conditions.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 37 (MC1DN37) [MIM:619272] 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. MC1DN37 features include developmental delay, cerebral atrophy, epilepsy, growth retardation, congenital myopathy with disproportion of fibers, and severely decreased activity of complex I. MC1DN37 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Contains four C-X9-C motifs that are predicted to form a helix-coil-helix structure, permitting the formation of intramolecular disulfide bonds.

Similarity. Belongs to the complex I NDUFA8 subunit family.

RefSeq proteins (1): NP_055037* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010625	CHCH	Domain
IPR016680	NDUFA8	Family

Pfam: PF06747

UniProt features (16 total): disulfide bond 4, short sequence motif 4, sequence variant 3, domain 2, initiator methionine 1, chain 1, region of interest 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-P51970-F1	93.88	0.89

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (4): 46–56, 78–110, 88–100, 36–66

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: 270 (showing top): STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, 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, KEGG_HUNTINGTONS_DISEASE

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 (3): NADH dehydrogenase (ubiquinone) activity (GO:0008137), protein-containing complex binding (GO:0044877), protein binding (GO:0005515)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial intermembrane space (GO:0005758), 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
binding	2
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
cellular respiration	1
mitochondrion	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 envelope lumen	1
NADH dehydrogenase complex	1
respiratory chain complex	1
transmembrane transporter complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3126 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFA8	NDUFA3	O95167	927
NDUFA8	NDUFB10	O96000	880
NDUFA8	NDUFA9	Q16795	856
NDUFA8	NDUFA13	Q9P0J0	842
NDUFA8	NDUFA5	Q16718	828
NDUFA8	NDUFB5	O43674	821
NDUFA8	NDUFS8	O00217	810
NDUFA8	NDUFS2	O75306	808
NDUFA8	NDUFB7	P17568	807
NDUFA8	NDUFA2	O43678	805
NDUFA8	NDUFA12	Q9UI09	792
NDUFA8	NDUFS5	O43920	791
NDUFA8	NDUFS3	O75489	785
NDUFA8	NDUFA7	O95182	770
NDUFA8	NDUFS6	O75380	768

IntAct

101 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFB5	NDUFB3	psi-mi:“MI:0914”(association)	0.640
NDUFAF4	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA9	NDUFS4	psi-mi:“MI:0914”(association)	0.640
NDUFA13	NDUFS8	psi-mi:“MI:0914”(association)	0.640
DMWD	NDUFA8	psi-mi:“MI:0915”(physical association)	0.560
SPRED1	NDUFA8	psi-mi:“MI:0915”(physical association)	0.560
NDUFS3	NDUFA8	psi-mi:“MI:0915”(physical association)	0.560
TIMMDC1	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFA8	NDUFS8	psi-mi:“MI:0914”(association)	0.530
ECSIT	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFV2	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFC2	NDUFS4	psi-mi:“MI:0914”(association)	0.530
NDUFB8	NDUFS4	psi-mi:“MI:0914”(association)	0.530
NDUFA12	NDUFS4	psi-mi:“MI:0914”(association)	0.530
NDUFB5	NDUFS7	psi-mi:“MI:0914”(association)	0.530
NDUFA9	NDUFS8	psi-mi:“MI:0914”(association)	0.530

BioGRID (306): NDUFA8 (Affinity Capture-MS), NDUFB1 (Affinity Capture-MS), NDUFV2 (Affinity Capture-MS), NDUFV3 (Affinity Capture-MS), CAMK2B (Affinity Capture-MS), CAMK2G (Affinity Capture-MS), CAMK2D (Affinity Capture-MS), ND4 (Affinity Capture-MS), NDUFAF1 (Affinity Capture-MS), NDUFA7 (Affinity Capture-MS), NDUFB9 (Affinity Capture-MS), NDUFA2 (Affinity Capture-MS), NDUFS2 (Affinity Capture-MS), NDUFA3 (Affinity Capture-MS), NDUFS1 (Affinity Capture-MS)

ESM2 similar proteins: A1L3N6, B5FXK1, O43715, O43920, P00429, P0CB87, P0CB88, P0CB91, P0CB92, P0CT19, P14854, P21976, P42029, P48504, P51970, P56277, P56391, Q02379, Q03015, Q0MQB0, Q0MQB1, Q0MQH3, Q0MQH4, Q0P451, Q28CA1, Q2NKR3, Q3ZCK8, Q49B96, Q4R374, Q4R3M6, Q53CG4, Q5RCT0, Q5RFJ0, Q5ZIN1, Q61908, Q6DHJ6, Q6YFP9, Q7YRK6, Q80ZN9, Q86WW8

Diamond homologs: P0CB91, P0CB92, P42029, P51970, Q0MQB0, Q0MQB1, Q8LGE7, Q9DCJ5, Q9SQT4, P21976

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NDUFA8	“form complex”	“NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I”	binding
TFEB	“up-regulates quantity by expression”	NDUFA8	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 96 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	24	58.4×	3e-35
Respiratory electron transport	26	36.4×	1e-32
Aerobic respiration and respiratory electron transport	24	31.2×	2e-28
Mitochondrial protein degradation	9	15.1×	5e-07

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	18	73.3×	1e-27
proton motive force-driven mitochondrial ATP synthesis	20	59.8×	3e-28
aerobic respiration	20	56.3×	6e-28
mitochondrial respiratory chain complex I assembly	12	56.0×	2e-16

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	30
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1064534	NM_014222.3(NDUFA8):c.139C>T (p.Arg47Cys)	Pathogenic
1064535	NM_014222.3(NDUFA8):c.293G>T (p.Arg98Leu)	Pathogenic
1679324	NM_014222.3(NDUFA8):c.403C>T (p.Arg135Ter)	Likely pathogenic

SpliceAI

450 predictions. Top by Δscore:

Variant	Effect	Δscore
9:122148108:TTACC:T	donor_loss	1.0000
9:122148109:TACC:T	donor_loss	1.0000
9:122148110:A:C	donor_loss	1.0000
9:122152267:TGTTG:T	donor_gain	1.0000
9:122152284:T:TA	donor_gain	1.0000
9:122144377:ACCT:A	acceptor_loss	0.9900
9:122144379:C:CC	acceptor_gain	0.9900
9:122144380:T:A	acceptor_loss	0.9900
9:122148274:CTGC:C	acceptor_gain	0.9900
9:122148275:TGC:T	acceptor_gain	0.9900
9:122148275:TGCC:T	acceptor_loss	0.9900
9:122148278:C:CC	acceptor_gain	0.9900
9:122148278:CTG:C	acceptor_loss	0.9900
9:122148279:T:A	acceptor_loss	0.9900
9:122159622:CTCAC:C	donor_loss	0.9900
9:122159624:CAC:C	donor_loss	0.9900
9:122159625:ACC:A	donor_loss	0.9900
9:122159626:C:A	donor_loss	0.9900
9:122159742:C:A	donor_gain	0.9900
9:122144388:G:C	acceptor_gain	0.9800
9:122144388:G:GC	acceptor_gain	0.9800
9:122148276:GC:G	acceptor_gain	0.9800
9:122148277:CC:C	acceptor_gain	0.9800
9:122152226:TGA:T	donor_gain	0.9800
9:122152239:TTTTA:T	donor_loss	0.9800
9:122152240:TTTAC:T	donor_loss	0.9800
9:122152241:TTAC:T	donor_loss	0.9800
9:122152242:TA:T	donor_loss	0.9800
9:122152243:AC:A	donor_loss	0.9800
9:122152244:C:A	donor_loss	0.9800

AlphaMissense

1126 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:122152331:A:C	F43L	0.997
9:122152331:A:T	F43L	0.997
9:122152333:A:G	F43L	0.997
9:122152353:C:G	C36S	0.997
9:122152354:A:T	C36S	0.997
9:122148260:C:T	C78Y	0.996
9:122148259:A:C	C78W	0.995
9:122152292:A:C	C56W	0.995
9:122152354:A:G	C36R	0.995
9:122152320:C:G	R47P	0.994
9:122152353:C:T	C36Y	0.994
9:122152377:G:T	A28E	0.994
9:122148194:C:G	C100S	0.993
9:122148195:A:T	C100S	0.993
9:122148260:C:G	C78S	0.993
9:122148261:A:G	C78R	0.993
9:122148261:A:T	C78S	0.993
9:122152293:C:T	C56Y	0.993
9:122152294:A:G	C56R	0.993
9:122152323:C:T	C46Y	0.993
9:122152326:A:G	L45P	0.993
9:122148193:A:C	C100W	0.992
9:122152293:C:G	C56S	0.992
9:122152294:A:T	C56S	0.992
9:122152322:G:C	C46W	0.992
9:122152323:C:G	C46S	0.992
9:122152324:A:T	C46S	0.992
9:122152352:A:C	C36W	0.992
9:122152353:C:A	C36F	0.992
9:122152374:G:T	A29D	0.992

dbSNP variants (sampled 300 via entrez): RS1000150238 (9:122137022 C>T), RS1000278827 (9:122159820 A>C,G,T), RS1000357653 (9:122134044 A>T), RS1000382584 (9:122140859 A>G), RS1000596144 (9:122133078 C>A,G), RS1000627886 (9:122153886 A>C,G,T), RS1000647580 (9:122134290 C>T), RS1000763465 (9:122135686 C>G), RS1000803349 (9:122138309 C>A), RS1000814029 (9:122135426 A>G), RS1000887852 (9:122145049 T>C), RS1000969830 (9:122142348 G>A), RS1001065254 (9:122148668 AG>A), RS1001067034 (9:122150787 T>C), RS1001252325 (9:122135485 G>A)

Disease associations

OMIM: gene MIM:603359 | disease phenotypes: MIM:619272

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 37	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Moderate	AR

Mondo (1): mitochondrial complex I deficiency, nuclear type 37 (MONDO:0030997)

Orphanet (0):

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000047	Hypospadias
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001662	Bradycardia
HP:0002059	Cerebral atrophy
HP:0002092	Pulmonary arterial hypertension
HP:0002098	Respiratory distress
HP:0002119	Ventriculomegaly
HP:0002120	Cerebral cortical atrophy
HP:0002133	Status epilepticus
HP:0002151	Increased circulating lactate concentration
HP:0002179	Opisthotonus
HP:0002401	Stroke-like episode
HP:0002421	Poor head control
HP:0002445	Tetraplegia
HP:0002490	Increased CSF lactate
HP:0003128	Lactic acidosis
HP:0003202	Skeletal muscle atrophy
HP:0003593	Infantile onset
HP:0007371	Corpus callosum atrophy

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001762_217	Obesity-related traits	6.000000e-06
GCST010725_17	Malaria	5.000000e-06
GCST010725_29	Malaria	1.000000e-06
GCST010725_96	Malaria	9.000000e-07
GCST90017148_4	Brain asymmetrical skew (vertical)	3.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004736	aspartate aminotransferase measurement
EFO:0004346	neuroimaging measurement

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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, affects cotreatment, increases expression, decreases expression	3
Acetaminophen	affects expression, affects cotreatment, increases expression	3
bisphenol A	affects cotreatment, affects expression, increases abundance, increases expression	2
Valproic Acid	affects expression, increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
ginger extract	affects expression, increases abundance, affects cotreatment	1
dicrotophos	decreases expression	1
arsenite	affects binding, increases reaction	1
ochratoxin A	affects cotreatment, decreases expression	1
benzo(e)pyrene	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
corosolic acid	decreases expression	1
K 7174	decreases expression	1
jinfukang	increases expression	1
Sunitinib	decreases expression	1
Air Pollutants, Occupational	decreases expression	1
Atrazine	decreases expression	1
Cadmium	increases abundance, increases expression	1
Citrinin	affects cotreatment, decreases expression	1
Doxorubicin	increases expression	1
Ivermectin	decreases expression	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Methapyrilene	decreases methylation	1
Nickel	decreases expression	1
Niclosamide	decreases expression	1
Oils, Volatile	affects cotreatment, affects expression, increases abundance	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)

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