NDUFA9

Summary

NDUFA9 (NADH:ubiquinone oxidoreductase subunit A9, HGNC:7693) is a protein-coding gene on chromosome 12p13.3, encoding NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial (Q16795). 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: 23.4% of cell lines).

The encoded protein is a subunit of the hydrophobic protein fraction of the NADH:ubiquinone oxidoreductase (complex I), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane. A pseudogene has been identified on chromosome 12.

Source: NCBI Gene 4704 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial complex I deficiency, nuclear type 26 (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 286 total — 7 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 23.4% of screened cell lines
• MANE Select transcript: NM_005002

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7693
Approved symbol	NDUFA9
Name	NADH:ubiquinone oxidoreductase subunit A9
Location	12p13.3
Locus type	gene with protein product
Status	Approved
Aliases	SDR22E1, CI-39k, COQ11
Ensembl gene	ENSG00000139180
Ensembl biotype	protein_coding
OMIM	603834
Entrez	4704

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 14 protein_coding, 5 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000266544, ENST00000396655, ENST00000535050, ENST00000535726, ENST00000539573, ENST00000540688, ENST00000542369, ENST00000544675, ENST00000544679, ENST00000852775, ENST00000852776, ENST00000852777, ENST00000852778, ENST00000852779, ENST00000852780, ENST00000852781, ENST00000911896, ENST00000911897, ENST00000943615, ENST00000943616

RefSeq mRNA: 1 — MANE Select: NM_005002 NM_005002

CCDS: CCDS8532

Canonical transcript exons

ENST00000266544 — 11 exons

Exon	Start	End
ENSE00002204942	4649114	4649175
ENSE00002309518	4686938	4694317
ENSE00003466489	4662533	4662635
ENSE00003501267	4668457	4668524
ENSE00003518227	4654292	4654462
ENSE00003522030	4669741	4669817
ENSE00003541027	4659036	4659177
ENSE00003554511	4657748	4657839
ENSE00003596336	4654825	4654922
ENSE00003613688	4685259	4685325
ENSE00003627020	4682205	4682300

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.4183 / max 265.9175, expressed in 1814 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
123580	22.4183	1814

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	98.64	gold quality
mucosa of transverse colon	UBERON:0004991	98.61	gold quality
heart left ventricle	UBERON:0002084	98.18	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.17	gold quality
cardiac ventricle	UBERON:0002082	98.15	gold quality
right atrium auricular region	UBERON:0006631	98.13	gold quality
rectum	UBERON:0001052	97.92	gold quality
gastrocnemius	UBERON:0001388	97.84	gold quality
transverse colon	UBERON:0001157	97.62	gold quality
muscle of leg	UBERON:0001383	97.40	gold quality
triceps brachii	UBERON:0001509	97.37	gold quality
heart right ventricle	UBERON:0002080	97.32	gold quality
metanephros cortex	UBERON:0010533	97.25	gold quality
heart	UBERON:0000948	97.03	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.94	gold quality
right adrenal gland cortex	UBERON:0035827	96.87	gold quality
right adrenal gland	UBERON:0001233	96.78	gold quality
body of stomach	UBERON:0001161	96.69	gold quality
duodenum	UBERON:0002114	96.65	gold quality
biceps brachii	UBERON:0001507	96.64	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.60	gold quality
large intestine	UBERON:0000059	96.57	gold quality
colon	UBERON:0001155	96.57	gold quality
intestine	UBERON:0000160	96.51	gold quality
body of tongue	UBERON:0011876	96.40	gold quality
left adrenal gland	UBERON:0001234	96.35	gold quality
small intestine	UBERON:0002108	96.33	gold quality
colonic epithelium	UBERON:0000397	96.32	gold quality
body of pancreas	UBERON:0001150	96.29	gold quality
stromal cell of endometrium	CL:0002255	96.22	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.87
E-CURD-112	yes	3.51

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

28 targeting NDUFA9, 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-5011-5P	100.00	83.46	5820
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3919	99.87	69.45	2489
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-4795-5P	99.11	66.90	876
HSA-MIR-4705	99.10	69.10	1091
HSA-MIR-3168	99.08	67.75	1384
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-3146	98.85	66.77	601
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-561-5P	98.25	68.13	1365
HSA-MIR-5087	98.01	69.09	965
HSA-MIR-4799-3P	97.78	65.97	893
HSA-MIR-4720-5P	97.46	65.67	893
HSA-MIR-5588-5P	97.46	65.70	913
HSA-MIR-6824-5P	97.41	68.43	583
HSA-MIR-509-3-5P	97.21	67.74	1517
HSA-MIR-509-5P	97.21	67.90	1512
HSA-MIR-4418	97.04	67.16	1372
HSA-MIR-4661-3P	96.81	66.02	342
HSA-MIR-4714-3P	96.53	67.44	452

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 23.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• Study identifies mitochondrial transit peptide and determines mature protein cleavage site in cow ortholog. (PMID:1832859)
• A pathogenic mutation was found in the complex I subunit encoding the NDUFA9 gene, changing a highly conserved arginine at position 321 to proline (PMID:22114105)
• NDUFA9 protein is essential for stabilizing the junction between membrane and matrix arms of complex I. (PMID:23223238)
• Additive effect of DNAJC30 and NDUFA9 mutations causing Leigh syndrome. (PMID:36939934)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufa9a	ENSDARG00000070723
danio_rerio	ndufa9b	ENSDARG00000094312
mus_musculus	Ndufa9	ENSMUSG00000000399
rattus_norvegicus	Ndufa9	ENSRNOG00000061684
drosophila_melanogaster	ND-39	FBGN0037001
caenorhabditis_elegans		WBGENE00021800

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial — Q16795 (reviewed: Q16795)

Alternative names: Complex I-39kD, NADH-ubiquinone oxidoreductase 39 kDa subunit

All UniProt accessions (3): Q16795, F5GY40, F5H0J3

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. 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. Complex I is composed of 45 different subunits. This a component of the hydrophobic protein fraction. Interacts with BLOC1S1. Interacts with SLC2A4. Interacts with CLOCK. Interacts with RAB5IF.

Subcellular location. Mitochondrion matrix.

Post-translational modifications. Acetylated on lysine residues. BLOC1S1 is required for acetylation. Acetylated by CLOCK in a circadian manner.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 26 (MC1DN26) [MIM:618247] 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. MC1DN26 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 FAD per subunit.

Similarity. Belongs to the complex I NDUFA9 subunit family.

RefSeq proteins (1): NP_004993* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001509	Epimerase_deHydtase	Domain
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR051207	ComplexI_NDUFA9_subunit	Family

Pfam: PF01370

UniProt features (38 total): helix 17, strand 10, turn 4, modified residue 3, sequence variant 2, transit peptide 1, chain 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-Q16795-F1	90.19	0.86

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 (3): 175, 189, 370

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: 280 (showing top): GOBP_CIRCADIAN_RHYTHM, MODULE_77, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_KETONE_METABOLIC_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_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, KORKOLA_EMBRYONAL_CARCINOMA_UP, GOBP_ATP_BIOSYNTHETIC_PROCESS, GOBP_OXIDATIVE_PHOSPHORYLATION

GO Biological Process (7): mitochondrial electron transport, NADH to ubiquinone (GO:0006120), ubiquinone biosynthetic process (GO:0006744), sodium ion transport (GO:0006814), circadian rhythm (GO:0007623), aerobic respiration (GO:0009060), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), proton transmembrane transport (GO:1902600)

GO Molecular Function (4): NADH dehydrogenase activity (GO:0003954), NADH dehydrogenase (ubiquinone) activity (GO:0008137), protein-containing complex binding (GO:0044877), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), mitochondrial membrane (GO:0031966), respiratory chain complex I (GO:0045271)

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	3
binding	2
intracellular membrane-bounded organelle	2
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
ubiquinone metabolic process	1
quinone biosynthetic process	1
metal ion transport	1
rhythmic process	1
cellular respiration	1
oxidative phosphorylation	1
proton motive force-driven ATP synthesis	1
monoatomic cation transmembrane transport	1
oxidoreductase activity, acting on NAD(P)H	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
organelle inner membrane	1
mitochondrial membrane	1
intracellular organelle lumen	1
mitochondrial envelope	1
organelle membrane	1
NADH dehydrogenase complex	1
respiratory chain complex	1
transmembrane transporter complex	1

Protein interactions and networks

STRING

3306 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFA9	NDUFS3	O75489	992
NDUFA9	NDUFS7	O75251	968
NDUFA9	NDUFA6	P56556	961
NDUFA9	SIRT3	Q9NTG7	960
NDUFA9	NDUFV2	P19404	949
NDUFA9	NDUFB6	O95139	942
NDUFA9	NDUFS1	P28331	934
NDUFA9	NDUFA2	O43678	926
NDUFA9	NDUFV1	P49821	921
NDUFA9	NDUFS2	O75306	914
NDUFA9	UQCRC2	P22695	890
NDUFA9	NDUFA10	O95299	887
NDUFA9	SDHA	P31040	886
NDUFA9	NDUFB10	O96000	881
NDUFA9	NDUFB8	O95169	880

IntAct

183 interactions, top by confidence:

A	B	Type	Score
NDUFA9	NDUFS2	psi-mi:“MI:0915”(physical association)	0.740
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
NDUFV2	NDUFS2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
HTT	NDUFA9	psi-mi:“MI:0915”(physical association)	0.670
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFS3	NDUFB6	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
NDUFAF1	NDUFS5	psi-mi:“MI:0914”(association)	0.640
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610

BioGRID (487): NDUFA9 (Affinity Capture-MS), NDUFA9 (Affinity Capture-MS), NDUFA9 (Affinity Capture-MS), NDUFA9 (Affinity Capture-MS), NDUFA9 (Affinity Capture-MS), AFG3L2 (Co-fractionation), ATP6V1C1 (Co-fractionation), IQGAP1 (Co-fractionation), NDUFA6 (Co-fractionation), NDUFA9 (Co-fractionation), NDUFA9 (Co-fractionation), NDUFA9 (Co-fractionation), NDUFA9 (Co-fractionation), NDUFA9 (Co-fractionation), NDUFA9 (Co-fractionation)

ESM2 similar proteins: A3R052, A8DZE7, A8E5C5, O35296, O35469, O46516, O88736, P0CB81, P0CB82, P14060, P14893, P22071, P22072, P24815, P26149, P26150, P26439, P27364, P27365, P56937, Q0IH28, Q0IH73, Q0MQB3, Q0MQB4, Q0VFE7, Q15738, Q16795, Q32L94, Q3ZBE9, Q4R7R1, Q566S6, Q5IFP1, Q5PPL3, Q5R6U1, Q5RJY4, Q60555, Q61694, Q61767, Q62878, Q62904

Diamond homologs: A0A0H3C8X7, H1ZZB0, P0CB81, P0CB82, P25284, P34943, P48279, P73212, Q0MQB3, Q0MQB4, Q16795, Q5BK63, Q60A54, Q6BLA6, Q9DC69, Q9H2F3, Q9SK66, A1CTL5, A1CYD8, A1DMU2, A1YER2, A1YFX9, A2QWW3, A2T7G9, A3LQJ9, A3LSB6, A3LUX6, A5DEZ6, A5DSN1, B0BNF8, P0C5D8, P40008, P45469, Q0CI32, Q0CZ00, Q1E7Y1, Q2TXI3, Q2UMY4, Q4WMS0, Q5AP65

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NDUFA9	“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 164 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	36.8×	3e-32
Respiratory electron transport	29	23.6×	4e-30
Aerobic respiration and respiratory electron transport	26	19.7×	1e-24
Mitochondrial protein degradation	12	11.7×	5e-08
Complex IV assembly	6	11.7×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	22	54.8×	3e-31
aerobic respiration	27	46.5×	7e-36
proton motive force-driven mitochondrial ATP synthesis	24	43.9×	3e-31
mitochondrial respiratory chain complex I assembly	13	37.1×	3e-15

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	5
Uncertain significance	133
Likely benign	72
Benign	40

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
2229490	NM_005002.5(NDUFA9):c.394C>T (p.Arg132Ter)	Pathogenic
30391	NM_005002.5(NDUFA9):c.962G>C (p.Arg321Pro)	Pathogenic
3375138	NM_005002.5(NDUFA9):c.895C>T (p.Arg299Ter)	Pathogenic
4690255	NM_005002.5(NDUFA9):c.710A>T (p.Lys237Ile)	Pathogenic
4690256	NM_005002.5(NDUFA9):c.1069C>G (p.Arg357Gly)	Pathogenic
4690257	NM_005002.5(NDUFA9):c.800G>T (p.Gly267Val)	Pathogenic
4690259	NM_005002.5(NDUFA9):c.1078C>G (p.Arg360Gly)	Pathogenic
3234875	NM_005002.5(NDUFA9):c.267T>A (p.Tyr89Ter)	Likely pathogenic
3895836	NM_005002.5(NDUFA9):c.552+1_552+5del	Likely pathogenic
4687641	NM_005002.5(NDUFA9):c.897-1G>C	Likely pathogenic
806977	GRCh37/hg19 12p13.32(chr12:4758264-4796274)x1	Likely pathogenic
996908	NM_005002.5(NDUFA9):c.938G>A (p.Trp313Ter)	Likely pathogenic

SpliceAI

1706 predictions. Top by Δscore:

Variant	Effect	Δscore
12:4654458:CCTTG:C	donor_gain	1.0000
12:4654459:CTTG:C	donor_gain	1.0000
12:4654460:TTG:T	donor_gain	1.0000
12:4654461:TGGTA:T	donor_loss	1.0000
12:4654462:GGTA:G	donor_loss	1.0000
12:4654463:G:GA	donor_loss	1.0000
12:4654463:G:GG	donor_gain	1.0000
12:4654464:T:A	donor_loss	1.0000
12:4654820:TTTA:T	acceptor_loss	1.0000
12:4654821:TTA:T	acceptor_loss	1.0000
12:4654822:TA:T	acceptor_loss	1.0000
12:4654822:TAG:T	acceptor_loss	1.0000
12:4654823:A:AG	acceptor_gain	1.0000
12:4654823:A:AT	acceptor_loss	1.0000
12:4654823:AGG:A	acceptor_loss	1.0000
12:4654824:G:GG	acceptor_gain	1.0000
12:4654918:TTCTG:T	donor_loss	1.0000
12:4654919:TCTGG:T	donor_loss	1.0000
12:4654920:CTGGT:C	donor_loss	1.0000
12:4654921:TGGTA:T	donor_loss	1.0000
12:4654923:G:C	donor_loss	1.0000
12:4654924:T:G	donor_loss	1.0000
12:4656511:GACTT:G	donor_gain	1.0000
12:4657737:T:A	acceptor_gain	1.0000
12:4657743:TATAG:T	acceptor_loss	1.0000
12:4657744:ATAGG:A	acceptor_loss	1.0000
12:4657745:TAGGA:T	acceptor_loss	1.0000
12:4657746:A:AG	acceptor_gain	1.0000
12:4657746:AG:A	acceptor_gain	1.0000
12:4657746:AGG:A	acceptor_loss	1.0000

AlphaMissense

2457 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:4654438:G:T	G66W	0.992
12:4657813:T:A	N128K	0.991
12:4657813:T:G	N128K	0.991
12:4657806:T:A	V126D	0.990
12:4657796:A:C	S123R	0.989
12:4657798:C:A	S123R	0.989
12:4657798:C:G	S123R	0.989
12:4657815:T:C	L129P	0.989
12:4654415:T:A	V58E	0.988
12:4654451:T:A	V70D	0.988
12:4662611:G:C	D211H	0.988
12:4654409:C:A	A56D	0.987
12:4654421:G:A	G60E	0.987
12:4668512:A:C	K237N	0.987
12:4668512:A:T	K237N	0.987
12:4659083:C:A	A153D	0.986
12:4662603:G:A	G208E	0.986
12:4669759:G:A	G248R	0.986
12:4669759:G:C	G248R	0.986
12:4659177:G:C	K184N	0.985
12:4659177:G:T	K184N	0.985
12:4669751:T:A	V245E	0.985
12:4687043:C:A	R357S	0.985
12:4687044:G:C	R357P	0.985
12:4654448:T:A	V69D	0.984
12:4654460:T:C	L73P	0.983
12:4657751:T:A	W108R	0.983
12:4657751:T:C	W108R	0.983
12:4654438:G:A	G66R	0.981
12:4654438:G:C	G66R	0.981

dbSNP variants (sampled 300 via entrez): RS1000041979 (12:4655961 A>T), RS1000136223 (12:4655685 TAGAAC>T), RS1000196408 (12:4678904 A>G), RS1000196927 (12:4676268 G>A), RS1000270616 (12:4676554 A>G), RS1000291225 (12:4678665 T>C), RS1000522364 (12:4680951 C>G), RS1000530682 (12:4680355 G>A), RS1000626369 (12:4672062 G>A,T), RS1000830962 (12:4686428 T>TG), RS1000896596 (12:4671157 A>G), RS1000904771 (12:4694605 G>C,T), RS1000932457 (12:4665597 G>A,C), RS1000984880 (12:4665885 T>A,C), RS1001053160 (12:4660247 C>T)

Disease associations

OMIM: gene MIM:603834 | disease phenotypes: MIM:256000, MIM:618247

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 26	Strong	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive
Leigh syndrome	Limited	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 (3): Leigh syndrome (MONDO:0009723), mitochondrial complex I deficiency, nuclear type 26 (MONDO:0032630), (MONDO:0016815)

Orphanet (1): Leigh syndrome (Orphanet:506)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000510	Rod-cone dystrophy
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001266	Choreoathetosis
HP:0001272	Cerebellar atrophy
HP:0001332	Dystonia
HP:0001942	Metabolic acidosis
HP:0002015	Dysphagia
HP:0002059	Cerebral atrophy
HP:0002093	Respiratory insufficiency
HP:0002151	Increased circulating lactate concentration
HP:0002353	EEG abnormality
HP:0002509	Limb hypertonia
HP:0003623	Neonatal onset
HP:0003648	Lacticaciduria
HP:0003693	Distal amyotrophy
HP:0011923	Decreased activity of mitochondrial complex I
HP:0032653	Elevated lactate:pyruvate ratio
HP:0034295	Reduced cerebral white matter volume

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003875_10	Gut microbiota (bacterial taxa)	7.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement
EFO:0007883	taxonomic microbiome measurement

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

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	2
Valproic Acid	affects expression, decreases methylation	2
aristolochic acid I	increases expression	1
ME-143	increases degradation	1
GSK-J4	increases expression	1
ME-344	increases degradation	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
bisphenol A	increases expression	1
beta-lapachone	decreases expression	1
arsenite	increases reaction, affects binding	1
perfluorooctanoic acid	decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
bisphenol B	increases expression	1
bisphenol AF	increases expression	1
Arsenic Trioxide	increases expression	1
Cannabidiol	decreases expression	1
Doxorubicin	affects expression	1
Flavin-Adenine Dinucleotide	affects binding, increases activity	1
Isoniazid	decreases expression	1
Ivermectin	decreases expression	1
Paraquat	decreases expression	1
Phenobarbital	affects expression	1
Rotenone	increases expression	1
Thimerosal	increases expression	1
Tretinoin	affects cotreatment, increases expression	1
Zidovudine	increases expression	1
1-Methyl-4-phenylpyridinium	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

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TA14	HAP1 NDUFA9 (-) 1	Cancer cell line	Male
CVCL_TA15	HAP1 NDUFA9 (-) 2	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