NDUFA6

Summary

NDUFA6 (NADH:ubiquinone oxidoreductase subunit A6, HGNC:7690) is a protein-coding gene on chromosome 22q13.2, encoding NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6 (P56556). Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed to be not involved in catalysis. It is a selective cancer dependency (DepMap: 47.8% of cell lines).

This gene encodes a member of the LYR family of proteins that contain a highly conserved tripeptide (LYR) motif near the N-terminus. The encoded protein is an accessory subunit of NADH: ubiquinone oxidorerductase (Complex I), which is the largest enzyme of the mitochondrial membrane respiratory chain. Complex I functions in electron transfer from NADH to the respiratory chain.

Source: NCBI Gene 4700 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial complex I deficiency, nuclear type 33 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 87 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 71
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 47.8% of screened cell lines
• MANE Select transcript: NM_002490

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7690
Approved symbol	NDUFA6
Name	NADH:ubiquinone oxidoreductase subunit A6
Location	22q13.2
Locus type	gene with protein product
Status	Approved
Aliases	B14, LYRM6, CI-B14, NADHB14
Ensembl gene	ENSG00000184983
Ensembl biotype	protein_coding
OMIM	602138
Entrez	4700

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000470753, ENST00000498737, ENST00000617763, ENST00000874890, ENST00000874891

RefSeq mRNA: 1 — MANE Select: NM_002490 NM_002490

CCDS: CCDS33656

Canonical transcript exons

ENST00000498737 — 3 exons

Exon	Start	End
ENSE00001296436	42090606	42090772
ENSE00001912575	42085526	42086314
ENSE00002220602	42087060	42087175

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 77.0600 / max 647.3953, expressed in 1828 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194409	76.4236	1828
194408	0.6364	281

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	98.93	gold quality
heart left ventricle	UBERON:0002084	98.72	gold quality
right atrium auricular region	UBERON:0006631	98.56	gold quality
apex of heart	UBERON:0002098	98.50	gold quality
heart	UBERON:0000948	98.31	gold quality
muscle of leg	UBERON:0001383	98.27	gold quality
gastrocnemius	UBERON:0001388	98.22	gold quality
skeletal muscle tissue	UBERON:0001134	98.19	gold quality
adult mammalian kidney	UBERON:0000082	97.92	gold quality
mucosa of transverse colon	UBERON:0004991	97.77	gold quality
ganglionic eminence	UBERON:0004023	97.71	gold quality
kidney	UBERON:0002113	97.60	gold quality
cortex of kidney	UBERON:0001225	97.54	gold quality
muscle tissue	UBERON:0002385	97.44	gold quality
duodenum	UBERON:0002114	97.17	gold quality
rectum	UBERON:0001052	97.14	gold quality
lower esophagus	UBERON:0013473	97.09	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.09	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.03	gold quality
transverse colon	UBERON:0001157	97.01	gold quality
ventricular zone	UBERON:0003053	97.01	gold quality
calcaneal tendon	UBERON:0003701	96.99	gold quality
primary visual cortex	UBERON:0002436	96.98	gold quality
colon	UBERON:0001155	96.93	gold quality
monocyte	CL:0000576	96.90	gold quality
metanephros cortex	UBERON:0010533	96.90	gold quality
right adrenal gland	UBERON:0001233	96.83	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.80	gold quality
leukocyte	CL:0000738	96.78	gold quality
adrenal tissue	UBERON:0018303	96.78	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.79
E-GEOD-75367	no	421.87

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TEAD1

miRNA regulators (miRDB)

28 targeting NDUFA6, 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-3667-3P	99.99	67.17	1636
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-2113	99.58	71.22	1521
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-520F-5P	99.34	70.40	1632
HSA-MIR-6738-3P	99.03	67.14	1326
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-4742-5P	98.89	68.41	1542
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-26B-3P	98.71	67.49	1102
HSA-MIR-2117	98.48	67.97	1307
HSA-MIR-4252	98.45	66.37	987
HSA-MIR-649	97.96	67.21	704
HSA-MIR-500A-3P	97.60	67.48	595
HSA-MIR-6849-3P	97.25	64.57	1371
HSA-MIR-4732-3P	97.15	65.45	881
HSA-MIR-125A-3P	97.04	66.92	902
HSA-MIR-552-3P	96.68	64.12	1026
HSA-MIR-6085	96.57	64.11	621
HSA-MIR-6813-5P	94.68	64.20	588
HSA-MIR-3174	94.63	63.64	577
HSA-MIR-6720-3P	91.34	60.49	67

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 47.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 1)

• A missense variant in NDUFA6 confers schizophrenia risk by affecting YY1 binding and NAGA expression. (PMID:33931730)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufa6	ENSDARG00000038028
mus_musculus	Ndufa6	ENSMUSG00000022450
rattus_norvegicus	Ndufa6	ENSRNOG00000008569
drosophila_melanogaster	ND-B14	FBGN0033570
caenorhabditis_elegans		WBGENE00013308

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6 — P56556 (reviewed: P56556)

Alternative names: Complex I-B14, LYR motif-containing protein 6, NADH-ubiquinone oxidoreductase B14 subunit

All UniProt accessions (3): A0A2Y9D025, P56556, R4GN43

UniProt curated annotations — full annotation on UniProt →

Function. Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed to be not involved in catalysis. Required for proper complex I assembly. 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. Mammalian complex I is composed of 45 different subunits.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 33 (MC1DN33) [MIM:618253] 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. MC1DN33 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the complex I LYR family.

RefSeq proteins (1): NP_002481* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016488	NADH_Ub_cplx-1_asu_su-6	Family
IPR045299	Complex1_LYR_NDUFA6_LYRM6	Domain

Pfam: PF13233

UniProt features (14 total): helix 6, sequence variant 3, turn 2, chain 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
9I4I	ELECTRON MICROSCOPY	2.63
9TI4	ELECTRON MICROSCOPY	2.66
5XTB	ELECTRON MICROSCOPY	3.4
9CWT	ELECTRON MICROSCOPY	3.44
5XTD	ELECTRON MICROSCOPY	3.7
5XTH	ELECTRON MICROSCOPY	3.9
5XTI	ELECTRON MICROSCOPY	17.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56556-F1	88.62	0.68

Functional residue map

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

Post-translational modifications (1): 11

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: 351 (showing top): CLAUS_PGR_POSITIVE_MENINGIOMA_UP, TGCGCANK_UNKNOWN, 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, BROWNE_HCMV_INFECTION_48HR_DN, ONKEN_UVEAL_MELANOMA_UP, GOBP_ATP_BIOSYNTHETIC_PROCESS, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS

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), 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
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
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

2851 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFA6	NDUFA9	Q16795	961
NDUFA6	NDUFA7	O95182	953
NDUFA6	NDUFV2	P19404	953
NDUFA6	NDUFB6	O95139	929
NDUFA6	NDUFV1	P49821	929
NDUFA6	NDUFS1	P28331	920
NDUFA6	NDUFA2	O43678	916
NDUFA6	NDUFS6	O75380	914
NDUFA6	NDUFA5	Q16718	912
NDUFA6	NDUFB5	O43674	904
NDUFA6	NDUFB3	O43676	892
NDUFA6	NDUFS3	O75489	885
NDUFA6	IKBKB	O14920	877
NDUFA6	NDUFB8	O95169	868
NDUFA6	NDUFS8	O00217	859

IntAct

89 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
POLR1E	POLR1C	psi-mi:“MI:0914”(association)	0.670
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA13	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA9	NDUFS4	psi-mi:“MI:0914”(association)	0.640
NDUFAF1	NDUFS5	psi-mi:“MI:0914”(association)	0.640
NDUFS5	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFA9	NDUFS8	psi-mi:“MI:0914”(association)	0.530
TOM1L2	NDUFA6	psi-mi:“MI:0914”(association)	0.530
NDUFV2	NDUFS8	psi-mi:“MI:0914”(association)	0.530
DNAJC30	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFC2	NDUFS4	psi-mi:“MI:0914”(association)	0.530
HSCB	NDUFS8	psi-mi:“MI:0914”(association)	0.460
NDUFA2	NDUFS8	psi-mi:“MI:0915”(physical association)	0.400
HSPB2	NDUFA6	psi-mi:“MI:0915”(physical association)	0.370
NDUFA12	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFA11	NDUFS8	psi-mi:“MI:0914”(association)	0.350
VAPA		psi-mi:“MI:0914”(association)	0.350
GOLT1B		psi-mi:“MI:0914”(association)	0.350
NDUFA6	NDUFS8	psi-mi:“MI:0914”(association)	0.350

BioGRID (198): NDUFA6 (Co-fractionation), NDUFA6 (Co-fractionation), NDUFA6 (Co-fractionation), NDUFA6 (Co-fractionation), NDUFA6 (Co-fractionation), NDUFA6 (Co-fractionation), NDUFA6 (Two-hybrid), NDUFA6 (Affinity Capture-MS), NDUFA6 (Affinity Capture-MS), NDUFA6 (Affinity Capture-MS), NDUFA6 (Affinity Capture-MS), NDUFA6 (Affinity Capture-MS), NDUFA6 (Affinity Capture-MS), NDUFA6 (Affinity Capture-MS), NDUFA6 (Affinity Capture-MS)

ESM2 similar proteins: A0JPA6, A1C9A5, A1D9R4, A2R2Q4, A3LNG8, A4DA73, A5DH70, A5PLG0, A9UL63, B0YEJ3, B4F7A1, B5FZA8, B5X5U9, B5XD90, B6GWX1, B8JLQ0, B8MP27, C4Y4R9, C5DEI4, C9SBR9, O46098, P56556, P82116, Q02366, Q0CVW0, Q0MQA3, Q0MQA4, Q0MQA5, Q0P574, Q0UIG9, Q0VCG0, Q2M2S9, Q4QQY2, Q4SQJ2, Q4WHK3, Q5AX36, Q5BBH7, Q5REC3, Q5U5X0, Q5XIY4

Diamond homologs: P42114, P56556, Q02366, Q0MQA3, Q0MQA4, Q0MQA5, Q9CQZ5, Q9LHI0, Q54F42

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NDUFA6	“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 84 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	21	58.9×	1e-30
Respiratory electron transport	21	33.9×	3e-25
Aerobic respiration and respiratory electron transport	20	30.0×	5e-23
Mitochondrial protein degradation	7	13.6×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	17	82.4×	6e-27
proton motive force-driven mitochondrial ATP synthesis	20	71.2×	4e-30
aerobic respiration	19	63.6×	1e-27
mitochondrial respiratory chain complex I assembly	9	50.0×	2e-11

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	41
Likely benign	22
Benign	3

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
487475	NM_002490.6(NDUFA6):c.331_332del (p.Glu111fs)	Pathogenic
487477	NM_002490.6(NDUFA6):c.191G>C (p.Arg64Pro)	Pathogenic
487478	NM_002490.6(NDUFA6):c.265G>T (p.Glu89Ter)	Pathogenic
549666	NM_002490.6(NDUFA6):c.355del (p.Leu119fs)	Pathogenic
549665	NM_002490.6(NDUFA6):c.309del (p.Met104fs)	Likely pathogenic
565011	GRCh37/hg19 22q13.2(chr22:41849322-42756616)x3	Likely pathogenic

SpliceAI

580 predictions. Top by Δscore:

Variant	Effect	Δscore
22:42087055:GTTA:G	donor_loss	1.0000
22:42087056:TTACC:T	donor_loss	1.0000
22:42087057:TACCT:T	donor_loss	1.0000
22:42087058:ACCTT:A	donor_loss	1.0000
22:42087059:C:CA	donor_loss	1.0000
22:42087080:C:CT	donor_gain	1.0000
22:42087081:C:CT	donor_gain	1.0000
22:42087171:GTGCA:G	acceptor_gain	1.0000
22:42087172:TGCA:T	acceptor_gain	1.0000
22:42087173:GCA:G	acceptor_gain	1.0000
22:42087174:CA:C	acceptor_gain	1.0000
22:42087174:CAC:C	acceptor_gain	1.0000
22:42087176:C:CC	acceptor_gain	1.0000
22:42086313:CC:C	acceptor_gain	0.9900
22:42086313:CCCT:C	acceptor_loss	0.9900
22:42086314:CC:C	acceptor_gain	0.9900
22:42086314:CCTGA:C	acceptor_loss	0.9900
22:42086315:C:CA	acceptor_loss	0.9900
22:42086315:C:CC	acceptor_gain	0.9900
22:42086316:T:A	acceptor_loss	0.9900
22:42087058:A:AC	donor_gain	0.9900
22:42087059:C:CC	donor_gain	0.9900
22:42087062:TAATG:T	donor_gain	0.9900
22:42087063:AATGA:A	donor_gain	0.9900
22:42087083:C:A	donor_gain	0.9900
22:42087172:TGCAC:T	acceptor_gain	0.9900
22:42087173:GCAC:G	acceptor_gain	0.9900
22:42087174:CACT:C	acceptor_gain	0.9900
22:42087175:ACT:A	acceptor_gain	0.9900
22:42087176:C:CA	acceptor_gain	0.9900

AlphaMissense

849 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:42087114:A:C	F67L	0.994
22:42087114:A:T	F67L	0.994
22:42087116:A:G	F67L	0.994
22:42090630:A:G	W39R	0.994
22:42090630:A:T	W39R	0.994
22:42086204:G:C	F122L	0.993
22:42086204:G:T	F122L	0.993
22:42086206:A:G	F122L	0.993
22:42086216:G:C	F118L	0.993
22:42086216:G:T	F118L	0.993
22:42086218:A:G	F118L	0.993
22:42086314:C:G	G86R	0.993
22:42086314:C:T	G86R	0.993
22:42087127:A:T	V63D	0.993
22:42087115:A:G	F67S	0.991
22:42087140:C:G	G59R	0.990
22:42087140:C:T	G59R	0.990
22:42087124:C:G	R64P	0.989
22:42087139:C:T	G59E	0.989
22:42090623:C:G	R41P	0.989
22:42086301:A:G	L90P	0.988
22:42086262:A:T	V103D	0.987
22:42087067:A:T	V83D	0.987
22:42087136:C:G	R60P	0.986
22:42090662:G:T	A28D	0.986
22:42086249:G:C	F107L	0.985
22:42086249:G:T	F107L	0.985
22:42086251:A:G	F107L	0.985
22:42086281:A:G	W97R	0.985
22:42086281:A:T	W97R	0.985

dbSNP variants (sampled 300 via entrez): RS1000095851 (22:42089497 T>C), RS1000179293 (22:42089758 G>A,T), RS1000300707 (22:42089870 G>A,C), RS1000698414 (22:42089378 C>G,T), RS1001134358 (22:42088455 C>G,T), RS1001368627 (22:42090469 C>A,T), RS1001801961 (22:42090109 T>C), RS1002120592 (22:42087359 T>C), RS1002778237 (22:42088902 G>A,C,T), RS1003068468 (22:42091172 G>A), RS1003124812 (22:42085670 T>A,C), RS1003130611 (22:42090900 C>G,T), RS1003282514 (22:42085424 G>C), RS1003425718 (22:42090995 C>A,G), RS1003976525 (22:42086939 A>G)

Disease associations

OMIM: gene MIM:602138 | disease phenotypes: MIM:618253

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 33	Strong	Autosomal recessive
mitochondrial complex I deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Moderate	AR

Mondo (3): mitochondrial complex I deficiency, nuclear type 33 (MONDO:0032636), mitochondrial disease (MONDO:0044970), mitochondrial complex I deficiency (MONDO:0100133)

Orphanet (1): Mitochondrial disease (Orphanet:68380)

HPO phenotypes

71 total (30 of 71 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000114	Proximal tubulopathy
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000543	Optic disc pallor
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000737	Irritability
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:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001321	Cerebellar hypoplasia
HP:0001324	Muscle weakness
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001562	Oligohydramnios

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002539_95	Schizophrenia	2.000000e-09
GCST004364_23	Intelligence	3.000000e-10
GCST004364_5	Intelligence	3.000000e-10
GCST004521_160	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004521_244	Autism spectrum disorder or schizophrenia	4.000000e-09
GCST006803_13	Schizophrenia	2.000000e-14
GCST010002_83	Refractive error	2.000000e-27

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
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

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

Chemical	Actions (top 5)	PubMed papers
Atrazine	decreases expression	2
Valproic Acid	affects cotreatment, increases expression, decreases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
moringin	affects cotreatment, increases expression	1
dicrotophos	decreases expression	1
bisphenol A	increases expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects response to substance, affects expression	1
arsenite	affects binding, increases reaction	1
perfluorooctanoic acid	decreases expression	1
1-methyl-4-phenyl-2,3-dihydropyridinium	decreases expression	1
monomethylarsonous acid	decreases expression	1
bisphenol B	increases expression	1
bisphenol S	affects expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Acetaminophen	affects cotreatment, decreases expression	1
Cannabidiol	affects cotreatment, increases expression	1
Cisplatin	increases expression	1
Doxorubicin	decreases expression	1
Fluorouracil	affects expression	1
Hydralazine	affects cotreatment, increases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Tunicamycin	decreases expression	1
Zidovudine	increases expression	1
Cadmium Chloride	decreases expression	1
Thapsigargin	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

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1YE	Abcam HeLa NDUFA6 KO	Cancer cell line	Female

Clinical trials (associated diseases)

103 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
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
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).
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy
NCT00786539	Not specified	COMPLETED	Mitochondria Inborn Errors of Metabolism and ANT Defects in Mitochondria Diseases
NCT00829270	Not specified	COMPLETED	Economic and Medical Evaluation of the Whole Mitochondrial DNA Screening by Surveyor and Mitochips Techniques
NCT00831948	Not specified	UNKNOWN	Identification of Large-Scale Mutations of POLG Gene by QMPSF in Patients With Mitochondrial DNA Instability.
NCT01001585	Not specified	TERMINATED	Anesthetic Effects in Mitochondrial Disease
NCT01148550	Not specified	SUSPENDED	Longitudinal Study of Mitochondrial Hepatopathies