NDUFS8

Summary

NDUFS8 (NADH:ubiquinone oxidoreductase core subunit S8, HGNC:7715) is a protein-coding gene on chromosome 11q13.2, encoding NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial (O00217). Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. It is a selective cancer dependency (DepMap: 45.7% of cell lines).

This gene encodes a subunit of mitochondrial NADH:ubiquinone oxidoreductase, or Complex I, a multimeric enzyme of the respiratory chain responsible for NADH oxidation, ubiquinone reduction, and the ejection of protons from mitochondria. The encoded protein is involved in the binding of two of the six to eight iron-sulfur clusters of Complex I and, as such, is required in the electron transfer process. Mutations in this gene have been associated with Leigh syndrome.

Source: NCBI Gene 4728 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +4 more curated relationships
• Clinical variants (ClinVar): 162 total — 4 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 60
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 45.7% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_002496

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7715
Approved symbol	NDUFS8
Name	NADH:ubiquinone oxidoreductase core subunit S8
Location	11q13.2
Locus type	gene with protein product
Status	Approved
Aliases	TYKY, CI-23k
Ensembl gene	ENSG00000110717
Ensembl biotype	protein_coding
OMIM	602141
Entrez	4728

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 20 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000313468, ENST00000432321, ENST00000453471, ENST00000524810, ENST00000525419, ENST00000525628, ENST00000526339, ENST00000526446, ENST00000526542, ENST00000528492, ENST00000529645, ENST00000531228, ENST00000531282, ENST00000531796, ENST00000532399, ENST00000852151, ENST00000852152, ENST00000852153, ENST00000852154, ENST00000852155, ENST00000852156, ENST00000927555, ENST00000945140, ENST00000945141, ENST00000945142, ENST00000945143, ENST00000945144, ENST00000945145, ENST00000945146

RefSeq mRNA: 1 — MANE Select: NM_002496 NM_002496

CCDS: CCDS8176

Canonical transcript exons

ENST00000313468 — 7 exons

Exon	Start	End
ENSE00001201214	68030681	68030733
ENSE00003481431	68032286	68032336
ENSE00003500594	68032923	68033012
ENSE00003506750	68036462	68036644
ENSE00003572838	68033111	68033283
ENSE00003603080	68036253	68036381
ENSE00003632105	68032152	68032209

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 176.0744 / max 1909.3583, expressed in 1828 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115513	169.6935	1826
115512	3.4897	1552
115514	1.2538	940
115515	1.0616	787
115516	0.5758	328

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.31	gold quality
right adrenal gland	UBERON:0001233	99.27	gold quality
right adrenal gland cortex	UBERON:0035827	99.21	gold quality
left adrenal gland	UBERON:0001234	99.19	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.16	gold quality
left adrenal gland cortex	UBERON:0035825	99.16	gold quality
adrenal cortex	UBERON:0001235	98.99	gold quality
right atrium auricular region	UBERON:0006631	98.99	gold quality
heart left ventricle	UBERON:0002084	98.90	gold quality
cardiac ventricle	UBERON:0002082	98.87	gold quality
cardiac atrium	UBERON:0002081	98.74	gold quality
adrenal gland	UBERON:0002369	98.61	gold quality
gastrocnemius	UBERON:0001388	98.56	gold quality
mucosa of transverse colon	UBERON:0004991	98.55	gold quality
adenohypophysis	UBERON:0002196	98.50	gold quality
heart	UBERON:0000948	98.43	gold quality
lower esophagus	UBERON:0013473	98.34	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.34	gold quality
triceps brachii	UBERON:0001509	98.33	gold quality
metanephros cortex	UBERON:0010533	98.26	gold quality
body of stomach	UBERON:0001161	98.25	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.25	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.24	gold quality
heart right ventricle	UBERON:0002080	98.22	gold quality
nucleus accumbens	UBERON:0001882	98.18	gold quality
pituitary gland	UBERON:0000007	98.17	gold quality
caudate nucleus	UBERON:0001873	98.17	gold quality
lower esophagus mucosa	UBERON:0035834	98.09	gold quality
putamen	UBERON:0001874	98.07	gold quality
vastus lateralis	UBERON:0001379	98.03	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	10.31
E-MTAB-10596	no	508.75
E-HCAD-30	no	183.63
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FLCN, SP1, YY1

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 45.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 3)

• 2 new mutations (P85L upstream from the 2 cysteine motifs that coordinate the two [4Fe-4S] clusters which generate the complex I N2 clusters, & R138H between them)suggest that this subunit is essential for either the assembly or stability of complex I. (PMID:15159508)
• Results show that NDUFS8 protein and mRNA levels are up-regulated in lung neoplasm and correlate with poor overall survival. (PMID:27516145)
• The requirement of the mitochondrial protein NDUFS8 for angiogenesis. (PMID:38594244)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufs8a	ENSDARG00000051986
mus_musculus	Ndufs8	ENSMUSG00000059734
rattus_norvegicus	Ndufs8	ENSRNOG00000017446
drosophila_melanogaster	ND-23	FBGN0017567
caenorhabditis_elegans		WBGENE00020636

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial — O00217 (reviewed: O00217)

Alternative names: Complex I-23kD, NADH-ubiquinone oxidoreductase 23 kDa subunit, TYKY subunit

All UniProt accessions (9): O00217, E9PJY7, E9PKH6, E9PN51, E9PPW7, F8W9K7, H0YCB2, H0YDT4, Q08E91

UniProt curated annotations — full annotation on UniProt →

Function. Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. Essential for the catalytic activity and assembly of complex I.

Subunit / interactions. Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits. This is a component of the iron-sulfur (IP) fragment of the enzyme. Interacts with RAB5IF.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Expressed in all tissues with the highest level in heart and skeletal muscle and the lowest level in lung.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 2 (MC1DN2) [MIM:618222] 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. MC1DN2 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 2 [4Fe-4S] cluster.

Similarity. Belongs to the complex I 23 kDa subunit family.

RefSeq proteins (1): NP_002487* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010226	NADH_quinone_OxRdtase_chainI	Family
IPR017896	4Fe4S_Fe-S-bd	Domain
IPR017900	4Fe4S_Fe_S_CS	Conserved_site

Pfam: PF12838

Catalyzed reactions (Rhea), 1 shown:

• a ubiquinone + NADH + 5 H(+)(in) = a ubiquinol + NAD(+) + 4 H(+)(out) (RHEA:29091)

UniProt features (38 total): binding site 8, sequence variant 8, strand 8, helix 8, domain 2, turn 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-O00217-F1	88.73	0.77

Functional residue map

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

Ligand- & substrate-binding residues (8): 156; 160; 111; 114; 117; 121; 150; 153

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: 325 (showing top): MODULE_93, GGGNRMNNYCAT_UNKNOWN, MODULE_77, ENK_UV_RESPONSE_KERATINOCYTE_UP, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, chr11q13, 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

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 (8): NADH dehydrogenase (ubiquinone) activity (GO:0008137), oxidoreductase activity, acting on NAD(P)H (GO:0016651), metal ion binding (GO:0046872), 4 iron, 4 sulfur cluster binding (GO:0051539), NADH dehydrogenase activity (GO:0003954), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), 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
oxidoreductase activity	1
cation binding	1
iron-sulfur cluster binding	1
oxidoreductase activity, acting on NAD(P)H	1
binding	1
catalytic activity	1
metal cluster binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
intracellular organelle lumen	1
NADH dehydrogenase complex	1
respiratory chain complex	1
transmembrane transporter complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

4805 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFS8	NDUFS7	O75251	999
NDUFS8	NDUFS3	O75489	998
NDUFS8	NDUFS2	O75306	998
NDUFS8	NDUFV1	P49821	997
NDUFS8	NDUFS1	P28331	994
NDUFS8	NDUFV2	P19404	992
NDUFS8	NDUFS6	O75380	933
NDUFS8	NDUFS4	O43181	924
NDUFS8	MT-ND4	P03905	916
NDUFS8	NDUFA11	Q86Y39	912
NDUFS8	NDUFA7	O95182	908
NDUFS8	NDUFA2	O43678	906
NDUFS8	MT-ND5	P03915	902
NDUFS8	NDUFB8	O95169	893
NDUFS8	NDUFA5	Q16718	882

IntAct

136 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA13	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFAF4	NDUFS8	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
TIMMDC1	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFA8	NDUFS8	psi-mi:“MI:0914”(association)	0.530
ECSIT	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFV2	NDUFS8	psi-mi:“MI:0914”(association)	0.530

BioGRID (357): NDUFS8 (Affinity Capture-MS), NDUFS8 (Affinity Capture-MS), NDUFS8 (Affinity Capture-MS), AFG3L2 (Co-fractionation), CYC1 (Co-fractionation), NDUFA12 (Co-fractionation), NDUFS3 (Co-fractionation), NDUFS8 (Co-fractionation), NDUFS8 (Co-fractionation), NDUFS8 (Co-fractionation), PHB2 (Co-fractionation), RAB1A (Co-fractionation), RAB1B (Co-fractionation), SDHB (Co-fractionation), UQCRC2 (Co-fractionation)

ESM2 similar proteins: A1B486, A3PIX9, A8LIV0, B6ISX3, F1QH17, O00217, O21233, O24143, O43242, O76031, O95782, P0CB97, P0CB98, P17426, P29921, P42028, P42031, P55931, P80269, Q0APY2, Q0BSL0, Q0C1D6, Q0MQI2, Q0MQI3, Q12644, Q16134, Q163R7, Q1GIM9, Q1GTK7, Q22619, Q28943, Q28T58, Q2G5Z4, Q2KIG0, Q2NA74, Q2RU32, Q3J3F0, Q42599, Q5LPS9, Q5R7N3

Diamond homologs: A1B486, A1USX5, A3PIX9, A4YVK2, A5CFN6, A5EK90, A5VPZ1, A6X1M5, A7HY41, A7IP99, A8F2T4, A8GPY5, A8GTS0, A8GY32, A8I407, A8LIV0, A9IUN3, A9MAI7, A9W1M5, B0BVB0, B0CLD7, B0ULL2, B1LUM8, B1ZA38, B2IHV8, B2S551, B3CUK1, B5ZYM2, B6ISX3, B6JH51, B7KQ58, B8EIM5, B8IUV4, B9JVF4, C0RIE7, C3PLS5, C4K221, O00217, O21233, O24143

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NDUFS8	“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 98 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	66.2×	2e-40
Respiratory electron transport	24	35.1×	1e-29
Aerobic respiration and respiratory electron transport	24	32.7×	5e-29
Mitochondrial protein degradation	7	12.3×	8e-05

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	19	80.2×	3e-30
proton motive force-driven mitochondrial ATP synthesis	21	65.0×	7e-31
aerobic respiration	21	61.2×	2e-30
mitochondrial respiratory chain complex I assembly	11	53.2×	1e-14

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	14
Uncertain significance	71
Likely benign	39
Benign	10

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
2577373	NM_002496.4(NDUFS8):c.160C>T (p.Arg54Trp)	Pathogenic
39834	NM_002496.4(NDUFS8):c.476C>A (p.Ala159Asp)	Pathogenic
39835	NM_002496.4(NDUFS8):c.187G>C (p.Glu63Gln)	Pathogenic
7513	NM_002496.4(NDUFS8):c.254C>T (p.Pro85Leu)	Pathogenic
1804015	NM_002496.4(NDUFS8):c.170G>C (p.Arg57Pro)	Likely pathogenic
1806071	NM_002496.4(NDUFS8):c.325G>A (p.Glu109Lys)	Likely pathogenic
214838	NM_002496.4(NDUFS8):c.428A>T (p.Tyr143Phe)	Likely pathogenic
3063712	NM_002496.4(NDUFS8):c.372+1G>A	Likely pathogenic
3239117	NM_002496.4(NDUFS8):c.376A>G (p.Ile126Val)	Likely pathogenic
3239612	NM_002496.4(NDUFS8):c.220_372+130del	Likely pathogenic
3254824	NM_002496.4(NDUFS8):c.501+5G>A	Likely pathogenic
3767218	NM_002496.4(NDUFS8):c.304C>T (p.Arg102Cys)	Likely pathogenic
3767219	NM_002496.4(NDUFS8):c.342C>A (p.Cys114Ter)	Likely pathogenic
3911504	NM_002496.4(NDUFS8):c.310_320del (p.Tyr104fs)	Likely pathogenic
429610	NM_002496.4(NDUFS8):c.292G>A (p.Glu98Lys)	Likely pathogenic
429611	NM_002496.4(NDUFS8):c.436G>A (p.Asp146Asn)	Likely pathogenic
488561	NM_002496.4(NDUFS8):c.441G>C (p.Met147Ile)	Likely pathogenic
7511	NM_002496.4(NDUFS8):c.236C>T (p.Pro79Leu)	Likely pathogenic

SpliceAI

1011 predictions. Top by Δscore:

Variant	Effect	Δscore
11:68032280:TTGCA:T	acceptor_loss	1.0000
11:68032281:TGCAG:T	acceptor_loss	1.0000
11:68032282:GCA:G	acceptor_loss	1.0000
11:68032283:CAG:C	acceptor_loss	1.0000
11:68032284:A:AG	acceptor_gain	1.0000
11:68032285:G:A	acceptor_loss	1.0000
11:68032285:G:GC	acceptor_gain	1.0000
11:68032333:TACAG:T	donor_loss	1.0000
11:68032334:ACAG:A	donor_loss	1.0000
11:68032336:AG:A	donor_loss	1.0000
11:68032337:G:GG	donor_gain	1.0000
11:68032338:TGA:T	donor_loss	1.0000
11:68032922:GA:G	acceptor_gain	1.0000
11:68032922:GAGT:G	acceptor_gain	1.0000
11:68033009:CGAGG:C	donor_loss	1.0000
11:68033010:GAGGT:G	donor_loss	1.0000
11:68033011:AGG:A	donor_loss	1.0000
11:68033014:T:A	donor_loss	1.0000
11:68033106:CACA:C	acceptor_loss	1.0000
11:68033107:ACAGG:A	acceptor_loss	1.0000
11:68033108:CAGG:C	acceptor_loss	1.0000
11:68033110:GGCCT:G	acceptor_gain	1.0000
11:68033281:CAGG:C	donor_loss	1.0000
11:68033284:G:GA	donor_loss	1.0000
11:68033285:T:G	donor_loss	1.0000
11:68036352:G:GT	donor_gain	1.0000
11:68032284:AG:A	acceptor_gain	0.9900
11:68032285:GG:G	acceptor_gain	0.9900
11:68032285:GGA:G	acceptor_gain	0.9900
11:68032285:GGAC:G	acceptor_gain	0.9900

AlphaMissense

1364 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:68033201:G:A	G97E	1.000
11:68033242:T:C	C111R	1.000
11:68033243:G:A	C111Y	1.000
11:68033251:T:C	C114R	1.000
11:68033252:G:A	C114Y	1.000
11:68033260:T:C	C117R	1.000
11:68033261:G:A	C117Y	1.000
11:68033261:G:T	C117F	1.000
11:68033272:T:C	C121R	1.000
11:68033273:G:A	C121Y	1.000
11:68033274:C:G	C121W	1.000
11:68036257:T:A	I126N	1.000
11:68036257:T:G	I126S	1.000
11:68036263:T:A	I128N	1.000
11:68036307:T:C	Y143H	1.000
11:68036314:T:A	I145N	1.000
11:68036328:T:A	C150S	1.000
11:68036328:T:C	C150R	1.000
11:68036329:G:A	C150Y	1.000
11:68036329:G:C	C150S	1.000
11:68036329:G:T	C150F	1.000
11:68036330:C:G	C150W	1.000
11:68036337:T:C	C153R	1.000
11:68036338:G:A	C153Y	1.000
11:68036338:G:T	C153F	1.000
11:68036346:T:A	C156S	1.000
11:68036346:T:C	C156R	1.000
11:68036347:G:A	C156Y	1.000
11:68036347:G:C	C156S	1.000
11:68036348:C:G	C156W	1.000

dbSNP variants (sampled 300 via entrez): RS1000131766 (11:68033906 C>T), RS1000242508 (11:68028733 G>A,T), RS1000627782 (11:68034042 C>A), RS1001106647 (11:68030739 T>G), RS1001306592 (11:68034075 A>G), RS1001366954 (11:68035358 A>G), RS1001372598 (11:68029608 C>G), RS1001426532 (11:68029840 G>A), RS1001452655 (11:68029078 A>T), RS1002401364 (11:68033479 A>G), RS1002714490 (11:68033239 C>G,T), RS1003082980 (11:68035437 C>A), RS1003145859 (11:68030283 A>G), RS1003880836 (11:68036795 G>C), RS1003984336 (11:68031347 C>CT)

Disease associations

OMIM: gene MIM:602141 | disease phenotypes: MIM:256000, MIM:618222, MIM:252010

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 2	Definitive	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive
mitochondrial complex I deficiency	Supportive	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	Definitive	AR

Mondo (5): Leigh syndrome (MONDO:0009723), mitochondrial complex I deficiency, nuclear type 2 (MONDO:0032606), mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224), (MONDO:0016815), mitochondrial complex I deficiency (MONDO:0100133)

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

HPO phenotypes

60 total (30 of 60 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
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: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:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001288	Gait disturbance
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001348	Brisk reflexes
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001612	Weak cry
HP:0001639	Hypertrophic cardiomyopathy
HP:0001943	Hypoglycemia
HP:0002013	Vomiting

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

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
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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Valproic Acid	increases expression, increases methylation	3
bisphenol A	increases expression, decreases expression	2
Acetaminophen	affects cotreatment, decreases expression	2
cobaltous chloride	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
chloropicrin	decreases expression	1
K 7174	decreases expression	1
ICG 001	increases expression	1
dibutyldi(4-chlorobenzohydroxamato)tin(IV)	decreases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Temozolomide	decreases expression	1
Decitabine	increases expression	1
Vorinostat	increases expression	1
Air Pollutants	increases abundance, affects expression	1
Arsenic	increases abundance, increases expression	1
Cadmium	increases palmitoylation, decreases reaction, increases abundance	1
Cisplatin	affects response to substance	1
Coumestrol	decreases expression	1
Formaldehyde	increases expression	1
Isoniazid	decreases expression	1
Ivermectin	decreases expression	1
Lead	increases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Methotrexate	affects response to substance	1
Niclosamide	decreases expression	1
Ozone	increases abundance, affects 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: 1 transformed cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9L5	Ubigene HEK293 NDUFS8 KO	Transformed cell line	Female
CVCL_EQ45	6613	Finite cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
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