NDUFA12

Summary

NDUFA12 (NADH:ubiquinone oxidoreductase subunit A12, HGNC:23987) is a protein-coding gene on chromosome 12q22, encoding NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 (Q9UI09). Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.

This gene encodes a protein which is part of mitochondrial complex 1, part of the oxidative phosphorylation system in mitochondria. Complex 1 transfers electrons to ubiquinone from NADH which establishes a proton gradient for the generation of ATP. Mutations in this gene are associated with Leigh syndrome due to mitochondrial complex 1 deficiency. Pseudogenes of this gene are located on chromosomes 5 and 13. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 55967 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 112 total — 8 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 15
• Druggable target: yes
• MANE Select transcript: NM_018838

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23987
Approved symbol	NDUFA12
Name	NADH:ubiquinone oxidoreductase subunit A12
Location	12q22
Locus type	gene with protein product
Status	Approved
Aliases	DAP13, B17.2
Ensembl gene	ENSG00000184752
Ensembl biotype	protein_coding
OMIM	614530
Entrez	55967

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 6 protein_coding, 5 nonsense_mediated_decay, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000327772, ENST00000538372, ENST00000546788, ENST00000547157, ENST00000547447, ENST00000547986, ENST00000550187, ENST00000551991, ENST00000552205, ENST00000682903, ENST00000684171, ENST00000684522, ENST00000684558, ENST00000917665, ENST00000917666

RefSeq mRNA: 2 — MANE Select: NM_018838 NM_001258338, NM_018838

CCDS: CCDS58263, CCDS9050

Canonical transcript exons

ENST00000327772 — 4 exons

Exon	Start	End
ENSE00001303152	95002739	95002821
ENSE00002399607	95003595	95003697
ENSE00003500017	94994170	94994257
ENSE00003664566	94971333	94971620

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 99.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 88.9970 / max 810.0574, expressed in 1825 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
132717	88.6085	1825
132715	0.3885	183

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	99.73	gold quality
tibialis anterior	UBERON:0001385	99.69	gold quality
myocardium	UBERON:0002349	99.67	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.67	gold quality
heart right ventricle	UBERON:0002080	99.55	gold quality
deltoid	UBERON:0001476	99.54	gold quality
ileal mucosa	UBERON:0000331	99.52	gold quality
vastus lateralis	UBERON:0001379	99.49	gold quality
quadriceps femoris	UBERON:0001377	99.48	gold quality
biceps brachii	UBERON:0001507	99.25	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.15	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.12	gold quality
skeletal muscle tissue	UBERON:0001134	99.11	gold quality
cardiac ventricle	UBERON:0002082	99.09	gold quality
muscle tissue	UBERON:0002385	99.09	gold quality
cardiac atrium	UBERON:0002081	99.08	gold quality
heart left ventricle	UBERON:0002084	99.08	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.06	gold quality
right atrium auricular region	UBERON:0006631	99.04	gold quality
body of tongue	UBERON:0011876	99.00	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.97	gold quality
heart	UBERON:0000948	98.94	gold quality
palpebral conjunctiva	UBERON:0001812	98.93	gold quality
apex of heart	UBERON:0002098	98.91	gold quality
muscle of leg	UBERON:0001383	98.87	gold quality
gastrocnemius	UBERON:0001388	98.87	gold quality
esophagus squamous epithelium	UBERON:0006920	98.85	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.84	gold quality
gingival epithelium	UBERON:0001949	98.81	gold quality
colonic mucosa	UBERON:0000317	98.78	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	10.24
E-MTAB-7606	no	270.19
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting NDUFA12, 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-3680-3P	99.75	72.51	3095
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-3606-5P	99.31	69.67	1168
HSA-MIR-1257	98.97	68.02	1133
HSA-MIR-3611	98.76	68.76	1290
HSA-MIR-4790-3P	96.63	67.08	806

Literature-anchored findings (GeneRIF, showing 3)

• NDUFA3, NDUFA5 and NDUFA12 supernumerary subunits are necessary for complex I activity and biogenesis. (PMID:24717771)
• NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4(-/-) mice and Leigh syndrome patients: A stabilizing role for NDUFAF2. (PMID:32335026)
• Novel NDUFA12 variants are associated with isolated complex I defect and variable clinical manifestation. (PMID:33715266)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufa12	ENSDARG00000042469
mus_musculus	Ndufa12	ENSMUSG00000020022
rattus_norvegicus	Ndufa12	ENSRNOG00000007407
drosophila_melanogaster	ND-B17.2	FBGN0031436
caenorhabditis_elegans		WBGENE00022380

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 — Q9UI09 (reviewed: Q9UI09)

Alternative names: 13 kDa differentiation-associated protein, Complex I-B17.2, NADH-ubiquinone oxidoreductase subunit B17.2

All UniProt accessions (8): Q9UI09, A0A804HHX9, A0A804HJF8, A0A804HK60, F8VRD8, F8VXI1, H0YID5, H0YIT1

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.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 23 (MC1DN23) [MIM:618244] 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. MC1DN23 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. In NDUFA12-knockout cells, complex I assembly is not affected, probably due to substitution by the NDUFAF2 paralog.

Similarity. Belongs to the complex I NDUFA12 subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UI09-1	1	yes
Q9UI09-2	2

RefSeq proteins (2): NP_001245267, NP_061326* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007763	NDUFA12	Family

Pfam: PF05071

UniProt features (14 total): strand 4, helix 4, sequence variant 2, chain 1, modified residue 1, turn 1, splice variant 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-Q9UI09-F1	96.01	0.99

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): 1

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: 205 (showing top): GCM_NPM1, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, HSIAO_HOUSEKEEPING_GENES, 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, GCM_PSME1, GCM_PPP1CC, GOBP_ATP_BIOSYNTHETIC_PROCESS, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS

GO Biological Process (4): aerobic respiration (GO:0009060), mitochondrial ATP synthesis coupled electron transport (GO:0042775), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), proton transmembrane transport (GO:1902600)

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

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), 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
cellular respiration	1
ATP synthesis coupled electron transport	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
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
NADH dehydrogenase complex	1
respiratory chain complex	1
transmembrane transporter complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2614 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFA12	NDUFAF2	Q8N183	963
NDUFA12	NDUFV1	P49821	919
NDUFA12	NDUFS1	P28331	885
NDUFA12	NDUFS4	O43181	863
NDUFA12	NDUFV3	P56181	852
NDUFA12	NDUFV2	P19404	844
NDUFA12	NDUFS2	O75306	833
NDUFA12	NDUFS8	O00217	829
NDUFA12	NDUFS6	O75380	828
NDUFA12	NDUFA7	O95182	826
NDUFA12	NDUFA2	O43678	814
NDUFA12	NDUFA6	P56556	811
NDUFA12	NDUFS7	O75251	801
NDUFA12	NDUFA8	P51970	792
NDUFA12	NDUFA5	Q16718	784

IntAct

147 interactions, top by confidence:

A	B	Type	Score
NDUFAF1	NDUFS3	psi-mi:“MI:0914”(association)	0.790
BAIAP2	YWHAQ	psi-mi:“MI:0914”(association)	0.740
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
NDUFV2	NDUFS2	psi-mi:“MI:0914”(association)	0.730
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
TUBA1C	TXNDC9	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA13	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA9	NDUFS4	psi-mi:“MI:0914”(association)	0.640
MYO15B	NDUFA12	psi-mi:“MI:0915”(physical association)	0.560
SYT4	NDUFA12	psi-mi:“MI:0915”(physical association)	0.560
TMED8	NDUFA12	psi-mi:“MI:0915”(physical association)	0.560
NDUFS5	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFA9	NDUFS8	psi-mi:“MI:0914”(association)	0.530
TIMMDC1	NDUFS8	psi-mi:“MI:0914”(association)	0.530
C3AR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530

BioGRID (307): NDUFA12 (Affinity Capture-MS), NDUFA12 (Affinity Capture-MS), NDUFA12 (Co-fractionation), NDUFA12 (Co-fractionation), NDUFA12 (Co-fractionation), NDUFA12 (Co-fractionation), NDUFA12 (Co-fractionation), NDUFA12 (Co-fractionation), NDUFA12 (Co-fractionation), NDUFA12 (Co-fractionation), NDUFA12 (Co-fractionation), NDUFA12 (Co-fractionation), NDUFA12 (Co-fractionation), NDUFA12 (Co-fractionation), NDUFA12 (Co-fractionation)

ESM2 similar proteins: A4FUH5, A8WJ42, A8X871, B4GDB3, B4NXN5, B5DZ31, C3ZWH9, C4A0P0, H2KYU6, O13962, O74988, O77460, O97725, P00428, P12075, P19536, P53077, P53700, P91929, Q00873, Q0MQ85, Q0MQ86, Q0MQ87, Q0WT48, Q20716, Q28FI8, Q32P65, Q54MV7, Q59J78, Q5ACH7, Q5R4R9, Q6BY05, Q6C9I7, Q6CG53, Q7TMF3, Q7XVN7, Q8MYM9, Q8N183, Q95QZ9, Q95Y89

Diamond homologs: O97725, Q0MQ85, Q0MQ86, Q0MQ87, Q54MV7, Q6CG53, Q7TMF3, Q9M9M9, Q9N2W7, Q9UI09, Q9ZCK4, Q8N183

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
NDUFA12	“form complex”	“NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I”	binding
CDK1	“up-regulates activity”	NDUFA12	phosphorylation
CyclinB/CDK1	“up-regulates activity”	NDUFA12	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 132 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	26	51.9×	7e-37
Respiratory electron transport	25	28.7×	3e-28
Aerobic respiration and respiratory electron transport	24	25.6×	7e-26
Mitochondrial protein degradation	10	13.8×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	22	69.8×	2e-33
proton motive force-driven mitochondrial ATP synthesis	23	53.6×	4e-32
aerobic respiration	23	50.4×	1e-31
mitochondrial respiratory chain complex I assembly	12	43.6×	6e-15

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	4
Uncertain significance	46
Likely benign	37
Benign	12

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1220537	NM_018838.5(NDUFA12):c.86G>A (p.Arg29Lys)	Pathogenic
1220538	NM_018838.5(NDUFA12):c.395del (p.Lys132fs)	Pathogenic
1220539	NM_018838.5(NDUFA12):c.224G>A (p.Trp75Ter)	Pathogenic
1352574	NM_018838.5(NDUFA12):c.13C>T (p.Gln5Ter)	Pathogenic
1687005	NM_018838.5(NDUFA12):c.83del (p.Phe28fs)	Pathogenic
2156716	NM_018838.5(NDUFA12):c.61del (p.Arg21fs)	Pathogenic
31207	NM_018838.5(NDUFA12):c.178C>T (p.Arg60Ter)	Pathogenic
3339658	NM_018838.5(NDUFA12):c.5del (p.Glu2fs)	Pathogenic
1308939	NM_018838.5(NDUFA12):c.1A>G (p.Met1Val)	Likely pathogenic
2143469	NM_018838.5(NDUFA12):c.169+1G>A	Likely pathogenic
4081534	NM_018838.5(NDUFA12):c.168dup (p.Gly57fs)	Likely pathogenic
800980	NM_018838.5(NDUFA12):c.4G>T (p.Glu2Ter)	Likely pathogenic

SpliceAI

829 predictions. Top by Δscore:

Variant	Effect	Δscore
12:95002735:TCACC:T	donor_loss	1.0000
12:95002736:CA:C	donor_loss	1.0000
12:95002737:A:AC	donor_gain	1.0000
12:95002738:C:CA	donor_loss	1.0000
12:95002738:C:CC	donor_gain	1.0000
12:95002738:CCAAA:C	donor_gain	1.0000
12:95002817:TTGTC:T	acceptor_gain	1.0000
12:95002818:TGTC:T	acceptor_gain	1.0000
12:95002819:GTC:G	acceptor_gain	1.0000
12:95002820:TC:T	acceptor_gain	1.0000
12:95002821:CC:C	acceptor_gain	1.0000
12:95002822:C:CC	acceptor_gain	1.0000
12:95002822:CTGTG:C	acceptor_loss	1.0000
12:95002823:T:G	acceptor_loss	1.0000
12:95002824:G:C	acceptor_gain	1.0000
12:95002828:A:AC	acceptor_gain	1.0000
12:95002833:C:CT	acceptor_gain	1.0000
12:95002833:C:T	acceptor_gain	1.0000
12:95002834:A:T	acceptor_gain	1.0000
12:95003591:CTACC:C	donor_loss	1.0000
12:95003592:TACC:T	donor_loss	1.0000
12:95003593:ACCTG:A	donor_loss	1.0000
12:94971620:CCT:C	acceptor_gain	0.9900
12:94971622:T:C	acceptor_gain	0.9900
12:95002737:AC:A	donor_gain	0.9900
12:95002738:CC:C	donor_gain	0.9900
12:95002738:CCA:C	donor_gain	0.9900
12:95002738:CCAA:C	donor_gain	0.9900
12:95002824:G:GC	acceptor_gain	0.9900
12:95002828:A:C	acceptor_gain	0.9900

AlphaMissense

951 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:94994171:A:G	W86R	0.992
12:94994171:A:T	W86R	0.992
12:94994248:C:G	R60P	0.992
12:94971613:A:G	W89R	0.990
12:94971613:A:T	W89R	0.990
12:94971469:A:G	W137R	0.988
12:94971469:A:T	W137R	0.988
12:95002784:C:G	D42H	0.988
12:94971611:C:A	W89C	0.987
12:94971611:C:G	W89C	0.987
12:94971554:G:C	F108L	0.986
12:94971554:G:T	F108L	0.986
12:94971556:A:G	F108L	0.986
12:94971467:C:A	W137C	0.984
12:94971467:C:G	W137C	0.984
12:94994187:G:C	S80R	0.984
12:94994187:G:T	S80R	0.984
12:94994189:T:G	S80R	0.984
12:95002782:G:C	D42E	0.984
12:95002782:G:T	D42E	0.984
12:95002783:T:G	D42A	0.984
12:94994242:A:T	V62D	0.983
12:95002766:A:G	Y48H	0.983
12:94994249:G:C	R60G	0.980
12:95002765:T:G	Y48S	0.980
12:95002783:T:A	D42V	0.979
12:94971609:A:G	L90P	0.978
12:95002770:G:C	N46K	0.978
12:95002770:G:T	N46K	0.978
12:94994246:A:G	W61R	0.976

dbSNP variants (sampled 300 via entrez): RS1000018482 (12:95001782 G>A), RS1000102385 (12:95000834 A>T), RS1000362746 (12:94971040 C>G,T), RS1000363701 (12:94982005 T>C), RS1000559882 (12:94997196 C>G,T), RS1000589685 (12:94997005 C>G), RS1000605159 (12:94984893 G>A), RS1000623549 (12:95003300 G>A), RS1000697278 (12:94983611 A>G), RS1000979129 (12:94977235 A>C), RS1000984845 (12:94972674 G>T), RS1001086740 (12:94970859 G>A,C), RS1001237678 (12:94994859 C>A), RS1001248785 (12:95000897 G>A), RS1001390837 (12:94971853 C>A)

Disease associations

OMIM: gene MIM:614530 | disease phenotypes: MIM:618244, MIM:256000, MIM:300896

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 23	Definitive	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Leigh syndrome	Limited	AR
mitochondrial disease	Definitive	AR

Mondo (4): mitochondrial complex I deficiency, nuclear type 23 (MONDO:0032627), Leigh syndrome (MONDO:0009723), SLC35A2-congenital disorder of glycosylation (MONDO:0010478), (MONDO:0016815)

Orphanet (2): Leigh syndrome (Orphanet:506), SLC35A2-CDG (Orphanet:356961)

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000998	Hypertrichosis
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001510	Growth delay
HP:0002151	Increased circulating lactate concentration
HP:0002490	Increased CSF lactate
HP:0002650	Scoliosis
HP:0003202	Skeletal muscle atrophy
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0011923	Decreased activity of mitochondrial complex I
HP:0031936	Delayed ability to walk

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST005196_68	Coronary artery disease	1.000000e-08
GCST008944_4	Chromosomal aberration frequency (chromosome type)	4.000000e-06
GCST010479_27	Coronary artery disease	2.000000e-08
GCST010703_206	Brain morphology (MOSTest)	1.000000e-11
GCST011365_144	Myocardial infarction	2.000000e-06
GCST012489_20	Heel bone mineral density x serum urate levels interaction	8.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0009861	chromosome-type aberration frequency
EFO:0004346	neuroimaging measurement
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density

MeSH disease descriptors (1)

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

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

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

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	3
bisphenol A	decreases expression, increases expression	2
sodium arsenite	increases abundance, increases expression	2
Air Pollutants	increases abundance, decreases expression, affects expression	2
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
perfluorooctanoic acid	decreases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	affects expression	1
bisphenol B	increases expression	1
gardiquimod	decreases expression, decreases reaction	1
bisphenol AF	increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases expression	1
Acetaminophen	affects cotreatment, decreases expression, increases expression	1
Arsenic	increases abundance, increases expression	1
Atrazine	increases expression	1
Cadmium	increases abundance, increases expression	1
Diuron	decreases expression	1
Doxorubicin	increases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Isoniazid	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Menthol	increases expression	1
Ozone	affects expression, increases abundance	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Smoke	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

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1P0	Abcam K-562 NDUFA12 KO	Cancer cell line	Female
CVCL_D2KK	Abcam Raji NDUFA12 KO	Cancer cell line	Male
CVCL_WQ02	Abcam Jurkat NDUFA12 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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