NDUFC2

Summary

NDUFC2 (NADH:ubiquinone oxidoreductase subunit C2, HGNC:7706) is a protein-coding gene on chromosome 11q14.1, encoding NADH dehydrogenase [ubiquinone] 1 subunit C2 (O95298). Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis but required for the complex assembly. It is a selective cancer dependency (DepMap: 34.5% of cell lines).

Predicted to enable NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial respiratory chain complex I assembly. Located in mitochondrial inner membrane. Part of respiratory chain complex I. Implicated in nuclear type mitochondrial complex I deficiency.

Source: NCBI Gene 4718 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leigh syndrome (Moderate, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 7 total
• Phenotypes (HPO): 22
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 34.5% of screened cell lines
• MANE Select transcript: NM_004549

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7706
Approved symbol	NDUFC2
Name	NADH:ubiquinone oxidoreductase subunit C2
Location	11q14.1
Locus type	gene with protein product
Status	Approved
Aliases	B14.5b, HLC-1
Ensembl gene	ENSG00000151366
Ensembl biotype	protein_coding
OMIM	603845
Entrez	4718

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000281031, ENST00000525085, ENST00000527806, ENST00000528164, ENST00000534029, ENST00000896454

RefSeq mRNA: 3 — MANE Select: NM_004549 NM_001204054, NM_001204055, NM_004549

CCDS: CCDS55779, CCDS55781, CCDS8257

Canonical transcript exons

ENST00000281031 — 3 exons

Exon	Start	End
ENSE00001424059	78068297	78070036
ENSE00001642011	78079579	78079862
ENSE00003498557	78072998	78073141

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 99.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.1452 / max 96.5111, expressed in 1771 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121462	143.1772	1827
121463	4.5476	1689
121461	2.0356	949
121464	0.5378	216
121465	0.0243	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	99.20	gold quality
left adrenal gland	UBERON:0001234	99.19	gold quality
left adrenal gland cortex	UBERON:0035825	99.19	gold quality
right adrenal gland cortex	UBERON:0035827	99.19	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.02	gold quality
mucosa of transverse colon	UBERON:0004991	98.91	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.91	gold quality
buccal mucosa cell	CL:0002336	98.87	gold quality
right lobe of thyroid gland	UBERON:0001119	98.87	gold quality
left lobe of thyroid gland	UBERON:0001120	98.86	gold quality
ganglionic eminence	UBERON:0004023	98.67	gold quality
right atrium auricular region	UBERON:0006631	98.58	gold quality
monocyte	CL:0000576	98.54	gold quality
right lobe of liver	UBERON:0001114	98.54	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.52	gold quality
adenohypophysis	UBERON:0002196	98.47	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.45	gold quality
cerebellar hemisphere	UBERON:0002245	98.41	gold quality
cerebellar cortex	UBERON:0002129	98.36	gold quality
gastrocnemius	UBERON:0001388	98.32	gold quality
left coronary artery	UBERON:0001626	98.31	gold quality
minor salivary gland	UBERON:0001830	98.31	gold quality
mononuclear cell	CL:0000842	98.28	gold quality
left uterine tube	UBERON:0001303	98.27	gold quality
adrenal gland	UBERON:0002369	98.21	gold quality
right frontal lobe	UBERON:0002810	98.21	gold quality
leukocyte	CL:0000738	98.20	gold quality
thyroid gland	UBERON:0002046	98.20	gold quality
right lung	UBERON:0002167	98.19	gold quality
anterior cingulate cortex	UBERON:0009835	98.19	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-75688	yes	574.08
E-GEOD-81383	no	1514.13
E-MTAB-7606	no	361.87
E-MTAB-9467	no	332.41
E-CURD-10	no	277.10
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

57 targeting NDUFC2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-7849-3P	99.47	68.17	1224
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-324-3P	99.26	66.31	1034
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-7974	99.24	65.48	1137
HSA-MIR-196A-3P	99.19	67.34	1204
HSA-MIR-505-3P	99.19	69.71	896
HSA-MIR-7151-3P	99.04	69.72	2370

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 34.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 9)

• NDUFC2 gene expression is decreased in both classic and follicular variants of papillary thyroid carcinoma. (PMID:21509594)
• DNA methylation of genes in retinol metabolism and calcium signaling pathways (P < 3 x 10-6) and with known functions in muscle and T2D including MEF2A, RUNX1, NDUFC2, and THADA decreased after exercise (PMID:23028138)
• Expression profiling of SCN8A and NDUFC2 genes in colorectal carcinoma is reported. There was no NDUFC2 differential expression in colorectal carcinoma. (PMID:25804238)
• Ndufc2 SNPs can contribute to an increased occurrence of early-onset ischemic stroke in humans. (PMID:26888427)
• Authors found that both fibroblasts obtained from skin of heterozygous Ndufc2 knock-out rat model showed marked mitochondrial dysfunction and human PBMC homozygous for the TT genotype of the rs11237379/NDUFC2 variant, previously shown to associate with reduced gene expression, demonstrated increased generation of reactive oxygen species and mitochondrial damage. (PMID:28973657)
• A significant reduction of NDUFC2 expression is detected in ACS. In vitro, NDUFC2 silencing affects vascular cell viability and angiogenesis while stimulating the expression of markers of plaque rupture. Our observations suggest that these mechanisms may contribute to ACS development. (PMID:30808603)
• Bi-allelic pathogenic variants in NDUFC2 cause early-onset Leigh syndrome and stalled biogenesis of complex I. (PMID:32969598)
• NDUFC2 deficiency exacerbates endothelial mesenchymal transformation during ischemia-reperfusion via NLRP3. (PMID:37506315)
• Polymorphic variants at NDUFC2, encoding a mitochondrial complex I subunit, associate with cardiac hypertrophy in human hypertension. (PMID:37558995)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufc2	ENSDARG00000102115
mus_musculus	Ndufc2	ENSMUSG00000030647
rattus_norvegicus	Ndufc2	ENSRNOG00000012383
drosophila_melanogaster	ND-B14.5B	FBGN0031505
caenorhabditis_elegans		WBGENE00022169

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] 1 subunit C2 — O95298 (reviewed: O95298)

Alternative names: Complex I-B14.5b, Human lung cancer oncogene 1 protein, NADH-ubiquinone oxidoreductase subunit B14.5b

All UniProt accessions (3): E9PM14, E9PRJ5, O95298

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 but required for the complex 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. Complex I is composed of 45 different subunits. Interacts with TMEM242.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 36 (MC1DN36) [MIM:619170] 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. MC1DN36 is characterized by global developmental delay, hypotonia, and failure to thrive apparent from infancy or early childhood. Affected individuals usually do not acquire ambulation, show progressive spasticity, and have impaired intellectual development with absent speech. MC1DN36 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 NDUFC2 subunit family.

Isoforms (4)

UniProt ID	Names	Canonical?
O95298-1	3	yes
O95298-2	4
O95298-3	5
E9PQ53-1	2, NDUFC2-KCTD14

RefSeq proteins (3): NP_001190983, NP_001190984, NP_004540* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009423	NDUC2	Family

Pfam: PF06374

UniProt features (6 total): splice variant 2, sequence variant 2, 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-O95298-F1	91.01	0.78

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-611105	Respiratory electron transport
R-HSA-6798695	Neutrophil degranulation
R-HSA-6799198	Complex I biogenesis
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 305 (showing top): WANG_CLIM2_TARGETS_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GOBP_NEGATIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, 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_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_REACTIVE_OXYGEN_SPECIES_BIOSYNTHETIC_PROCESS

GO Biological Process (9): mitochondrial electron transport, NADH to ubiquinone (GO:0006120), aerobic respiration (GO:0009060), positive regulation of mitochondrial membrane potential (GO:0010918), mitochondrial respiratory chain complex I assembly (GO:0032981), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), negative regulation of non-canonical NF-kappaB signal transduction (GO:1901223), negative regulation of reactive oxygen species biosynthetic process (GO:1903427), positive regulation of ATP biosynthetic process (GO:2001171), proton transmembrane transport (GO:1902600)

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

GO Cellular Component (7): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), plasma membrane (GO:0005886), azurophil granule membrane (GO:0035577), respiratory chain complex I (GO:0045271), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Innate Immune System	1
Respiratory electron transport	1
Metabolism	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
cellular respiration	1
positive regulation of membrane potential	1
regulation of mitochondrial membrane potential	1
NADH dehydrogenase complex assembly	1
mitochondrial respiratory chain complex assembly	1
mitochondrion	1
oxidative phosphorylation	1
proton motive force-driven ATP synthesis	1
non-canonical NF-kappaB signal transduction	1
regulation of non-canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
negative regulation of biosynthetic process	1
reactive oxygen species biosynthetic process	1
regulation of reactive oxygen species biosynthetic process	1
negative regulation of reactive oxygen species metabolic process	1
ATP biosynthetic process	1
positive regulation of purine nucleotide biosynthetic process	1
positive regulation of ATP metabolic process	1
regulation of ATP biosynthetic process	1
monoatomic cation transmembrane transport	1
NADH dehydrogenase activity	1
electron transfer activity	1
proton transmembrane transporter activity	1
oxidoreduction-driven active transmembrane transporter activity	1
oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor	1
active monoatomic ion transmembrane transporter activity	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
membrane	1
cell periphery	1
lysosomal membrane	1
secretory granule membrane	1
azurophil granule	1

Protein interactions and networks

STRING

1416 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFC2	NDUFA2	O43678	929
NDUFC2	NDUFC1	O43677	836
NDUFC2	NDUFB3	O43676	756
NDUFC2	NDUFA8	P51970	755
NDUFC2	NDUFA6	P56556	750
NDUFC2	NDUFS2	O75306	747
NDUFC2	NDUFS6	O75380	744
NDUFC2	NDUFB10	O96000	743
NDUFC2	NDUFB6	O95139	743
NDUFC2	NDUFV1	P49821	730
NDUFC2	NDUFA11	Q86Y39	727
NDUFC2	NDUFS5	O43920	717
NDUFC2	NDUFB8	O95169	717
NDUFC2	NDUFS7	O75251	712
NDUFC2	NDUFA5	Q16718	693

IntAct

99 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA13	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
ASPH	STXBP3	psi-mi:“MI:0914”(association)	0.640
NDUFA8	NDUFS8	psi-mi:“MI:0914”(association)	0.530
ECSIT	NDUFS8	psi-mi:“MI:0914”(association)	0.530
SPPL2B	UQCRQ	psi-mi:“MI:0914”(association)	0.530
TIMMDC1	NDUFC2	psi-mi:“MI:0914”(association)	0.530
C3AR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
NDUFS5	NDUFS4	psi-mi:“MI:0914”(association)	0.530
NDUFC2	NDUFS4	psi-mi:“MI:0914”(association)	0.530
DNAJC30	NDUFS8	psi-mi:“MI:0914”(association)	0.530
FUT1	NDUFS4	psi-mi:“MI:0914”(association)	0.530
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
PRRT2	NDUFS4	psi-mi:“MI:0914”(association)	0.530
NDUFA2	NDUFS8	psi-mi:“MI:0915”(physical association)	0.400
NDUFA13	SLC22A20P	psi-mi:“MI:0914”(association)	0.350
NDUFA6	NDUFS8	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350

BioGRID (124): NDUFC2 (Affinity Capture-MS), NDUFC2 (Affinity Capture-MS), NDUFC2 (Affinity Capture-MS), NDUFC2 (Affinity Capture-MS), NDUFC2 (Affinity Capture-MS), NDUFC2 (Affinity Capture-MS), NDUFC2 (Affinity Capture-MS), NDUFC2 (Affinity Capture-MS), NDUFC2 (Affinity Capture-MS), NDUFC2 (Affinity Capture-MS), NDUFC2 (Affinity Capture-MS), NDUFC2 (Affinity Capture-MS), NDUFC2 (Affinity Capture-MS), NDUFC2 (Affinity Capture-MS), NDUFC2 (Affinity Capture-MS)

ESM2 similar proteins: A1L2P2, A2VDV9, A5PJ82, D2H617, D3Z9R8, D4ACP2, E2R5I0, E7EXZ6, F6USH3, G1QDE8, G1S9B8, O00483, O95298, P11951, P14790, P56378, P56379, Q0MQ97, Q0MQ98, Q0MQ99, Q0MQF7, Q0MQF8, Q0MQF9, Q0Q4Z0, Q28EM2, Q28GF4, Q2NKS2, Q4FZG9, Q502E5, Q5BKW8, Q5RCY6, Q5RDZ8, Q5REX0, Q62425, Q68EV8, Q69YU5, Q78IK2, Q78RX3, Q7YRJ8, Q7YRK7

Diamond homologs: E9PQ53, O95298, Q02827, Q0MQF7, Q0MQF8, Q0MQF9, Q8SPI4, Q9CQ54

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NDUFC2	“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 108 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	23	49.4×	1e-31
Respiratory electron transport	24	29.7×	2e-27
Aerobic respiration and respiratory electron transport	21	24.1×	7e-22
Mitochondrial protein degradation	7	10.4×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	16	58.5×	4e-22
mitochondrial respiratory chain complex I assembly	13	54.5×	1e-17
proton motive force-driven mitochondrial ATP synthesis	17	45.7×	9e-22
aerobic respiration	17	43.0×	2e-21

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	2
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

322 predictions. Top by Δscore:

Variant	Effect	Δscore
11:78072987:A:C	donor_gain	1.0000
11:78072995:TA:T	donor_loss	1.0000
11:78072995:TACCT:T	donor_loss	1.0000
11:78072997:C:CT	donor_loss	1.0000
11:78072997:CCT:C	donor_loss	1.0000
11:78073000:T:A	donor_gain	1.0000
11:78079575:TCA:T	donor_loss	1.0000
11:78079575:TCACC:T	donor_loss	1.0000
11:78079576:CA:C	donor_loss	1.0000
11:78079577:A:AC	donor_gain	1.0000
11:78079577:A:T	donor_loss	1.0000
11:78079577:ACCAG:A	donor_gain	1.0000
11:78079578:C:CC	donor_gain	1.0000
11:78079578:C:CT	donor_gain	1.0000
11:78079578:CCAG:C	donor_gain	1.0000
11:78079578:CCAGC:C	donor_gain	1.0000
11:78072997:CCTT:C	donor_gain	0.9900
11:78073098:A:T	acceptor_gain	0.9900
11:78073137:CAAAC:C	acceptor_gain	0.9900
11:78073141:CCTGA:C	acceptor_loss	0.9900
11:78073142:C:G	acceptor_loss	0.9900
11:78073142:CTGAA:C	acceptor_loss	0.9900
11:78079573:ACTC:A	donor_loss	0.9900
11:78079577:AC:A	donor_gain	0.9900
11:78079578:CC:C	donor_gain	0.9900
11:78079578:CCA:C	donor_gain	0.9900
11:78069907:TCA:T	donor_gain	0.9800
11:78069910:A:C	donor_gain	0.9800
11:78070032:CTTAT:C	acceptor_gain	0.9800
11:78073142:C:CC	acceptor_gain	0.9800

AlphaMissense

767 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:78079636:C:G	G37R	0.992
11:78073080:T:A	K76N	0.991
11:78073080:T:G	K76N	0.991
11:78079635:C:T	G37D	0.991
11:78073008:A:C	F100L	0.987
11:78073008:A:T	F100L	0.987
11:78073010:A:G	F100L	0.987
11:78073096:C:T	G71E	0.987
11:78079610:G:C	N45K	0.987
11:78079610:G:T	N45K	0.987
11:78070002:G:C	F115L	0.985
11:78070002:G:T	F115L	0.985
11:78070004:A:G	F115L	0.985
11:78073022:G:C	H96D	0.985
11:78079644:C:T	G34D	0.985
11:78079645:C:G	G34R	0.985
11:78073097:C:G	G71R	0.984
11:78073097:C:T	G71R	0.984
11:78079630:A:G	C39R	0.982
11:78073111:G:T	A66D	0.981
11:78073114:G:T	T65K	0.980
11:78073133:G:T	R59S	0.980
11:78079623:C:T	G41D	0.979
11:78073132:C:G	R59P	0.978
11:78079624:C:G	G41R	0.978
11:78073081:T:A	K76I	0.977
11:78073136:G:C	H58D	0.974
11:78073114:G:C	T65R	0.973
11:78073099:G:T	A70D	0.972
11:78079633:A:C	Y38D	0.970

dbSNP variants (sampled 300 via entrez): RS1000019546 (11:78078036 A>G), RS1000191793 (11:78073701 C>T), RS1000301252 (11:78078311 A>T), RS1000350095 (11:78071669 A>T), RS1000650650 (11:78073343 T>C,G), RS1000683206 (11:78073093 T>A,C), RS1000751897 (11:78073471 G>A), RS1000769622 (11:78071968 T>C), RS1001143595 (11:78080085 C>G), RS1001194903 (11:78075266 TA>T,TAA,TAAA), RS1001234581 (11:78068512 C>T), RS1001308127 (11:78068678 G>A), RS1001603933 (11:78068733 C>T), RS1001735573 (11:78081479 T>A), RS1001739534 (11:78069043 C>A)

Disease associations

OMIM: gene MIM:603845 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 36	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Leigh syndrome	Moderate	AR
mitochondrial disease	Moderate	AR

Mondo (1): mitochondrial complex I deficiency, nuclear type 36 (MONDO:0030902)

Orphanet (0):

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000543	Optic disc pallor
HP:0000817	Reduced eye contact
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001640	Cardiomegaly
HP:0002151	Increased circulating lactate concentration
HP:0002280	Enlarged cisterna magna
HP:0002376	Developmental regression
HP:0002509	Limb hypertonia
HP:0002783	Recurrent lower respiratory tract infections
HP:0003348	Hyperalaninemia
HP:0003593	Infantile onset
HP:0006970	Periventricular leukomalacia
HP:0008358	Hyperprolinemia
HP:0008936	Axial hypotonia
HP:0011463	Childhood onset
HP:0011682	Perimembranous ventricular septal defect
HP:0011923	Decreased activity of mitochondrial complex I
HP:0030674	Antenatal onset

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005359_17	Disease progression in age-related macular degeneration	5.000000e-06
GCST007277_15	Tourette syndrome	5.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008336	disease progression 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

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, affects cotreatment, increases expression, affects expression	3
Acetaminophen	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
trichostatin A	affects expression, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
3-methyladenine	decreases expression, decreases reaction, affects cotreatment	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
1-nitropyrene	decreases expression, affects cotreatment, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
corosolic acid	decreases expression	1
bisphenol AF	increases expression	1
Vehicle Emissions	decreases expression	1
Cannabidiol	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Indomethacin	increases expression, affects cotreatment	1
Methapyrilene	decreases methylation	1
Nickel	affects expression, decreases reaction	1
Phenobarbital	affects expression	1
Polychlorinated Biphenyls	affects expression	1
Taurine	decreases expression, decreases reaction, affects cotreatment	1
Urethane	decreases expression	1
Vinblastine	affects response to substance	1
1-Methyl-3-isobutylxanthine	increases expression, affects cotreatment	1
Isotretinoin	decreases expression	1
Copper Sulfate	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

Clinical trials (associated diseases)

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