NDUFS6

Summary

NDUFS6 (NADH:ubiquinone oxidoreductase subunit S6, HGNC:7713) is a protein-coding gene on chromosome 5p15.33, encoding NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial (O75380). 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 subunit of the NADH:ubiquinone oxidoreductase (complex I), which is the first enzyme complex in the electron transport chain of mitochondria. This complex functions in the transfer of electrons from NADH to the respiratory chain. The subunit encoded by this gene is one of seven subunits in the iron-sulfur protein fraction. Mutations in this gene cause mitochondrial complex I deficiency, a disease that causes a wide variety of clinical disorders, including neonatal disease and adult-onset neurodegenerative disorders.

Source: NCBI Gene 4726 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 239 total — 12 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 44
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_004553

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7713
Approved symbol	NDUFS6
Name	NADH:ubiquinone oxidoreductase subunit S6
Location	5p15.33
Locus type	gene with protein product
Status	Approved
Aliases	CI-13kA
Ensembl gene	ENSG00000145494
Ensembl biotype	protein_coding
OMIM	603848
Entrez	4726

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000274137, ENST00000469176, ENST00000510329, ENST00000870776, ENST00000933860, ENST00000933861, ENST00000933862, ENST00000933863, ENST00000933864, ENST00000933865

RefSeq mRNA: 1 — MANE Select: NM_004553 NM_004553

CCDS: CCDS3866

Canonical transcript exons

ENST00000274137 — 4 exons

Exon	Start	End
ENSE00000970749	1802321	1802374
ENSE00000970750	1814339	1814461
ENSE00000999280	1815851	1816048
ENSE00001492867	1801407	1801549

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 141.9601 / max 847.5186, expressed in 1827 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
55579	141.9601	1827

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	99.37	gold quality
apex of heart	UBERON:0002098	99.23	gold quality
right atrium auricular region	UBERON:0006631	99.07	gold quality
gingival epithelium	UBERON:0001949	99.06	gold quality
mucosa of transverse colon	UBERON:0004991	99.05	gold quality
heart left ventricle	UBERON:0002084	99.01	gold quality
cardiac ventricle	UBERON:0002082	99.00	gold quality
endothelial cell	CL:0000115	98.85	gold quality
cervix squamous epithelium	UBERON:0006922	98.80	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.78	gold quality
gastrocnemius	UBERON:0001388	98.74	gold quality
gingiva	UBERON:0001828	98.72	gold quality
esophagus squamous epithelium	UBERON:0006920	98.68	gold quality
squamous epithelium	UBERON:0006914	98.64	gold quality
muscle of leg	UBERON:0001383	98.63	gold quality
heart right ventricle	UBERON:0002080	98.63	gold quality
heart	UBERON:0000948	98.61	gold quality
cardiac atrium	UBERON:0002081	98.57	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.38	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.29	gold quality
left testis	UBERON:0004533	98.28	gold quality
muscle organ	UBERON:0001630	98.26	gold quality
right testis	UBERON:0004534	98.26	gold quality
lower esophagus	UBERON:0013473	98.21	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.21	gold quality
transverse colon	UBERON:0001157	98.20	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.17	gold quality
body of stomach	UBERON:0001161	98.15	gold quality
biceps brachii	UBERON:0001507	98.13	gold quality
parietal pleura	UBERON:0002400	98.13	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-46	yes	10.86
E-MTAB-8530	no	1297.95
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

1 targeting NDUFS6, 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-3065-3P	99.87	70.25	1407

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 8)

• NDUFS6, a complex I subunit gene not previously associated with complex I deficiency, was grossly underexpressed in t patient cell lines. (PMID:15372108)
• NDUFS6 is required for the assembly and stabilization of a portion of complex I that contains a number of subunits. (PMID:17438127)
• This protein has been found differentially expressed in the temporal lobe from patients with schizophrenia. (PMID:19034380)
• CD147 appears to regulate complex I activity and apoptosis in malignant melanoma cells by interacting with mitochondrial NDUFS6. (PMID:25470292)
• Biallelic variants in two complex I genes cause abnormal splicing defects in probands with mild Leigh syndrome. (PMID:33097395)
• Adult mesenchymal stem cell ageing interplays with depressed mitochondrial Ndufs6. (PMID:33323934)
• PRMT1 methylation of WTAP promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6A modification of NDUFS6. (PMID:37558663)
• Alternative splicing expands the clinical spectrum of NDUFS6-related mitochondrial disorders. (PMID:38459834)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufs6	ENSDARG00000056583
mus_musculus	Ndufs6	ENSMUSG00000021606
rattus_norvegicus	Ndufs6-ps1	ENSRNOG00000018068
drosophila_melanogaster	ND-13A	FBGN0031684
caenorhabditis_elegans	nduf-6	WBGENE00009051

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial — O75380 (reviewed: O75380)

Alternative names: Complex I-13kD-A, NADH-ubiquinone oxidoreductase 13 kDa-A subunit

All UniProt accessions (3): O75380, D6RBT3, Q6IBC4

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. Mammalian complex I is composed of 45 different subunits. This is a component of the iron-sulfur (IP) fragment of the enzyme.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 9 (MC1DN9) [MIM:618232] 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. MC1DN9 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 NDUFS6 subunit family.

RefSeq proteins (1): NP_004544* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016668	NDUFS6	Family
IPR019401	Znf_CHCC	Domain

Pfam: PF10276

UniProt features (12 total): strand 6, helix 2, transit peptide 1, chain 1, modified residue 1, sequence 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-O75380-F1	82.60	0.67

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): 98

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: 347 (showing top): MODULE_93, ELVIDGE_HYPOXIA_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, MODULE_77, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_GROWTH, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CELLULAR_SENESCENCE, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_STEM_CELL_PROLIFERATION, GOBP_MONOATOMIC_CATION_TRANSPORT

GO Biological Process (21): kidney development (GO:0001822), mitochondrial electron transport, NADH to ubiquinone (GO:0006120), fatty acid metabolic process (GO:0006631), muscle contraction (GO:0006936), aerobic respiration (GO:0009060), gene expression (GO:0010467), stem cell division (GO:0017145), DNA damage response, signal transduction by p53 class mediator (GO:0030330), mitochondrial respiratory chain complex I assembly (GO:0032981), multicellular organism growth (GO:0035264), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), regulation of mitochondrial membrane potential (GO:0051881), reproductive system development (GO:0061458), circulatory system development (GO:0072359), mesenchymal stem cell differentiation (GO:0072497), reactive oxygen species metabolic process (GO:0072593), cellular senescence (GO:0090398), mesenchymal stem cell proliferation (GO:0097168), mitochondrion organization (GO:0007005), respiratory electron transport chain (GO:0022904), proton transmembrane transport (GO:1902600)

GO Molecular Function (2): NADH dehydrogenase (ubiquinone) activity (GO:0008137), electron transfer activity (GO:0009055)

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
cellular respiration	2
system development	2
animal organ development	1
renal system development	1
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
muscle system process	1
macromolecule biosynthetic process	1
cell division	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
NADH dehydrogenase complex assembly	1
mitochondrial respiratory chain complex assembly	1
multicellular organismal process	1
developmental growth	1
mitochondrion	1
oxidative phosphorylation	1
proton motive force-driven ATP synthesis	1
regulation of membrane potential	1
stem cell differentiation	1
metabolic process	1
cellular process	1
cellular response to stress	1
stem cell proliferation	1
organelle organization	1
electron transport chain	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
molecular_function	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
NADH dehydrogenase complex	1

Protein interactions and networks

STRING

2460 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFS6	NDUFS4	O43181	987
NDUFS6	NDUFV2	P19404	985
NDUFS6	NDUFS1	P28331	985
NDUFS6	NDUFV1	P49821	971
NDUFS6	NDUFS2	O75306	964
NDUFS6	NDUFS3	O75489	955
NDUFS6	NDUFA2	O43678	949
NDUFS6	NDUFA5	Q16718	945
NDUFS6	NDUFS7	O75251	944
NDUFS6	NDUFS8	O00217	933
NDUFS6	NDUFV3	P56181	931
NDUFS6	NDUFA6	P56556	914
NDUFS6	NDUFB5	O43674	901
NDUFS6	NDUFA1	O15239	894
NDUFS6	NDUFS5	O43920	894

IntAct

132 interactions, top by confidence:

A	B	Type	Score
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
NDUFS3	NDUFS8	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
SDHAF3	NDUFAB1	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
NDUFS5	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFA9	NDUFS8	psi-mi:“MI:0914”(association)	0.530
GDPD5	GOLIM4	psi-mi:“MI:0914”(association)	0.530
GALNT6	NDUFS4	psi-mi:“MI:0914”(association)	0.530
RASL10B	AHCYL1	psi-mi:“MI:0914”(association)	0.530
GCAT	NDUFS6	psi-mi:“MI:0914”(association)	0.530
MRM3	NDUFS6	psi-mi:“MI:0914”(association)	0.530
MSRB2	BLTP3B	psi-mi:“MI:0914”(association)	0.530
NDUFV2	NDUFS8	psi-mi:“MI:0914”(association)	0.530
RPS19BP1	DCTN6	psi-mi:“MI:0914”(association)	0.530
COX5B	COX7A2L	psi-mi:“MI:0914”(association)	0.530

BioGRID (363): NDUFS6 (Affinity Capture-RNA), NDUFS6 (Affinity Capture-RNA), NDUFS6 (Affinity Capture-MS), NDUFS6 (Affinity Capture-MS), NDUFS6 (Affinity Capture-MS), NDUFS6 (Affinity Capture-MS), NDUFS6 (Affinity Capture-MS), NDUFS6 (Affinity Capture-MS), NDUFS6 (Affinity Capture-MS), NDUFS6 (Affinity Capture-MS), NDUFS6 (Affinity Capture-MS), NDUFS6 (Affinity Capture-MS), NDUFS6 (Affinity Capture-MS), NDUFS6 (Affinity Capture-MS), NDUFV3 (Affinity Capture-MS)

ESM2 similar proteins: A3KN28, D2HZB0, F1QH17, O43181, O75208, O75380, O76031, O82597, O82793, O95453, P0CB95, P0CB96, P11029, P11497, P69341, P82670, Q02375, Q0IIL1, Q0MQH0, Q0MQH1, Q0MQH5, Q0MQH7, Q13085, Q1LZ96, Q28559, Q3UMR5, Q5R752, Q5R7N3, Q5RC51, Q5SRX1, Q5SWU9, Q5U2U0, Q5XIF3, Q66XS7, Q68FT1, Q68FW3, Q6P6Q9, Q80ZK0, Q8K1Z0, Q8K4P7

Diamond homologs: O75380, P23934, P52503, P52504, Q0MQH5, Q0MQH6, Q0MQH7, Q19724, Q4R5X8, Q5AUI1, Q9M9M6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NDUFS6	“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 116 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Complex I biogenesis	21	43.5×	1e-27
Respiratory electron transport	26	30.9×	3e-30
Aerobic respiration and respiratory electron transport	22	24.3×	4e-23
Complex IV assembly	7	20.0×	3e-06
Mitochondrial protein degradation	9	12.8×	2e-06
Cytoprotection by HMOX1	5	11.5×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	17	59.8×	2e-24
proton motive force-driven mitochondrial ATP synthesis	20	51.6×	6e-27
aerobic respiration	20	48.6×	1e-26
mitochondrial respiratory chain complex I assembly	8	32.2×	2e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	20
Uncertain significance	55
Likely benign	104
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1455958	NM_004553.6(NDUFS6):c.324_325del (p.Lys108fs)	Pathogenic
1460350	NC_000005.9:g.(?1801522)(1814585_?)del	Pathogenic
1703685	GRCh37/hg19 5p15.33-13.3(chr5:113576-29310520)	Pathogenic
2425150	NC_000005.9:g.(?1801522)(1802498_?)del	Pathogenic
2425151	NC_000005.9:g.(?1814443)(1816040_?)del	Pathogenic
2425153	NC_000005.9:g.(?1801522)(1816040_?)del	Pathogenic
2796111	NM_004553.6(NDUFS6):c.318_319del (p.Glu106fs)	Pathogenic
2843781	NM_004553.6(NDUFS6):c.274_275del (p.Gly92fs)	Pathogenic
2846883	NM_004553.6(NDUFS6):c.53_56del (p.Ala18fs)	Pathogenic
2995456	NM_004553.6(NDUFS6):c.71del (p.Gly24fs)	Pathogenic
6016	NM_004553.6(NDUFS6):c.186+2T>A	Pathogenic
6017	nsv1197507	Pathogenic
1497750	NM_004553.6(NDUFS6):c.288_292del (p.His96fs)	Likely pathogenic
1509610	NM_004553.6(NDUFS6):c.335dup (p.Cys112fs)	Likely pathogenic
2010865	NM_004553.6(NDUFS6):c.132+1G>C	Likely pathogenic
214824	NM_004553.6(NDUFS6):c.305A>T (p.Asn102Ile)	Likely pathogenic
2432093	NM_004553.6(NDUFS6):c.223C>T (p.Gln75Ter)	Likely pathogenic
2677000	NM_004553.6(NDUFS6):c.187-1G>C	Likely pathogenic
2677001	NM_004553.6(NDUFS6):c.314_315del (p.Lys105fs)	Likely pathogenic
2677003	NM_004553.6(NDUFS6):c.182_185del (p.Lys61fs)	Likely pathogenic
2677005	NM_004553.6(NDUFS6):c.302_303del (p.Ile101fs)	Likely pathogenic
2677006	NM_004553.6(NDUFS6):c.186+1G>A	Likely pathogenic
2700782	NM_004553.6(NDUFS6):c.187-2A>G	Likely pathogenic
3239851	NM_004553.6(NDUFS6):c.185_186del (p.Glu62fs)	Likely pathogenic
3239852	NM_004553.6(NDUFS6):c.187-2A>T	Likely pathogenic
3592192	NM_004553.6(NDUFS6):c.334_359delinsAACAAACAAAAA (p.Cys112fs)	Likely pathogenic
4081535	NM_004553.6(NDUFS6):c.187-38_223del	Likely pathogenic
4815357	NM_004553.6(NDUFS6):c.197dup (p.Asn66fs)	Likely pathogenic
4815358	NM_004553.6(NDUFS6):c.294del (p.Val99fs)	Likely pathogenic
4815359	NM_004553.6(NDUFS6):c.344G>T (p.Cys115Phe)	Likely pathogenic

SpliceAI

1091 predictions. Top by Δscore:

Variant	Effect	Δscore
5:1802316:TCCA:T	acceptor_loss	1.0000
5:1802317:CCAG:C	acceptor_loss	1.0000
5:1802318:CAGG:C	acceptor_loss	1.0000
5:1802319:A:AG	acceptor_gain	1.0000
5:1802320:G:GG	acceptor_gain	1.0000
5:1802320:G:T	acceptor_loss	1.0000
5:1802320:GGT:G	acceptor_gain	1.0000
5:1802320:GGTT:G	acceptor_gain	1.0000
5:1802320:GGTTT:G	acceptor_gain	1.0000
5:1802372:GAG:G	donor_gain	1.0000
5:1802373:AG:A	donor_loss	1.0000
5:1802374:GG:G	donor_loss	1.0000
5:1802376:T:A	donor_loss	1.0000
5:1802223:T:G	donor_gain	0.9900
5:1802319:AG:A	acceptor_gain	0.9900
5:1802320:GG:G	acceptor_gain	0.9900
5:1802378:AGTA:A	donor_loss	0.9900
5:1811063:G:GG	donor_gain	0.9900
5:1814405:A:AG	donor_gain	0.9900
5:1814447:GT:G	donor_gain	0.9900
5:1814461:GGT:G	donor_loss	0.9900
5:1814462:G:GA	donor_loss	0.9900
5:1814463:TGC:T	donor_loss	0.9900
5:1814464:GCG:G	donor_loss	0.9900
5:1815845:TTTCA:T	acceptor_loss	0.9900
5:1815846:TTCA:T	acceptor_loss	0.9900
5:1815847:TCAGG:T	acceptor_loss	0.9900
5:1815849:A:AG	acceptor_gain	0.9900
5:1815849:A:G	acceptor_loss	0.9900
5:1815850:G:GG	acceptor_gain	0.9900

AlphaMissense

805 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:1814438:C:G	H96D	0.996
5:1802354:T:C	F56L	0.995
5:1802356:T:A	F56L	0.995
5:1802356:T:G	F56L	0.995
5:1815881:T:C	Y114H	0.995
5:1814440:C:A	H96Q	0.994
5:1814440:C:G	H96Q	0.994
5:1815876:G:A	C112Y	0.994
5:1815896:T:C	F119L	0.994
5:1815898:C:A	F119L	0.994
5:1815898:C:G	F119L	0.994
5:1814412:G:A	C87Y	0.992
5:1815875:T:C	C112R	0.992
5:1814411:T:C	C87R	0.991
5:1815876:G:T	C112F	0.990
5:1815888:G:A	G116E	0.990
5:1815875:T:A	C112S	0.989
5:1815876:G:C	C112S	0.989
5:1815897:T:C	F119S	0.989
5:1802371:A:C	K61N	0.988
5:1802371:A:T	K61N	0.988
5:1814438:C:A	H96N	0.988
5:1814441:C:T	P97S	0.988
5:1814460:T:C	L103S	0.988
5:1815877:C:G	C112W	0.988
5:1815885:G:A	C115Y	0.988
5:1814411:T:A	C87S	0.987
5:1814412:G:C	C87S	0.987
5:1814436:G:A	G95D	0.987
5:1814454:T:A	I101K	0.987

dbSNP variants (sampled 300 via entrez): RS1000392603 (5:1814326 C>A,T), RS1000665905 (5:1810153 C>A), RS1000723574 (5:1815285 G>A,C,T), RS1000732230 (5:1809205 G>A), RS1000776482 (5:1815499 T>C), RS1000862727 (5:1805526 G>C), RS1001074191 (5:1800857 T>G), RS1001249869 (5:1803763 C>CAGTGAT), RS1001276985 (5:1811685 G>A), RS1001375025 (5:1801508 C>G,T), RS1001383961 (5:1808866 A>G), RS1001422176 (5:1800551 G>C,T), RS1001783800 (5:1801736 G>A), RS1001959970 (5:1800098 T>G), RS1002134995 (5:1816072 A>G)

Disease associations

OMIM: gene MIM:603848 | disease phenotypes: MIM:618232, MIM:123450, MIM:252010

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 9	Strong	Autosomal recessive
mitochondrial complex I deficiency, nuclear type	Moderate	Autosomal recessive
mitochondrial complex I deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (5): mitochondrial complex I deficiency, nuclear type 9 (MONDO:0032615), mitochondrial complex I deficiency (MONDO:0100133), Cri-du-chat syndrome (MONDO:0007404), mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224), (MONDO:0009640)

Orphanet (2): Isolated complex I deficiency (Orphanet:2609), Monosomy 5p syndrome (Orphanet:281)

HPO phenotypes

44 total (30 of 44 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:0001263	Global developmental delay
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001639	Hypertrophic cardiomyopathy
HP:0001943	Hypoglycemia
HP:0002013	Vomiting
HP:0002093	Respiratory insufficiency
HP:0002240	Hepatomegaly
HP:0002352	Leukoencephalopathy
HP:0002415	Leukodystrophy
HP:0002421	Poor head control
HP:0002490	Increased CSF lactate

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007626_4	Lack of perseverance	1.000000e-07
GCST009391_437	Metabolite levels	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006946	behavioural disinhibition measurement
EFO:0010385	phosphatidylcholine 38:3 measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003410	Cri-du-Chat Syndrome	C10.597.606.360.180; C16.131.077.262; C16.131.260.190; C16.320.180.190
C537475	Mitochondrial complex I deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363065 (PROTEIN COMPLEX), CHEMBL6067012 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

10 potent at pChembl≥5 of 20 total, top 10 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
5.50	Kd	3154	nM	CHEMBL5653589
5.50	ED50	3154	nM	CHEMBL5653589
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

9 with measured affinity, of 30 total; 5 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148855: Binding affinity to human NDUFS6 incubated for 45 mins by Kinobead based pull down assay	kd	3.1544	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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Acetaminophen	affects cotreatment, decreases expression	3
bisphenol A	decreases expression, increases expression	2
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects response to substance, affects expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	decreases expression, decreases reaction	1
arsenite	affects binding, increases reaction	1
methylparaben	decreases expression	1
perfluorooctanoic acid	decreases expression	1
ochratoxin A	increases expression	1
tris(chloroethyl)phosphate	decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
corosolic acid	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
Arsenic	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Dactinomycin	affects cotreatment, increases secretion	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Flame Retardants	decreases expression, increases abundance	1
Colforsin	decreases expression, decreases reaction	1
Indomethacin	affects cotreatment, increases expression	1
Isoniazid	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Phenobarbital	affects expression	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Valproic Acid	increases methylation	1

ChEMBL screening assays

5 unique, capped per target: 5 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)

4 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)
NCT01238250	Not specified	RECRUITING	Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight
NCT02381457	Not specified	COMPLETED	SNP-based Microdeletion and Aneuploidy RegisTry (SMART)
NCT06740162	Not specified	RECRUITING	Physical Activity and Community EmPOWERment Project