NDUFAF2

Summary

NDUFAF2 (NADH:ubiquinone oxidoreductase complex assembly factor 2, HGNC:28086) is a protein-coding gene on chromosome 5q12.1, encoding NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 2 (Q8N183). Acts as a molecular chaperone for mitochondrial complex I assembly.

NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. This gene encodes a complex I assembly factor. Mutations in this gene cause progressive encephalopathy resulting from mitochondrial complex I deficiency.

Source: NCBI Gene 91942 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leigh syndrome (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 14
• Clinical variants (ClinVar): 163 total — 14 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 53
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_174889

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28086
Approved symbol	NDUFAF2
Name	NADH:ubiquinone oxidoreductase complex assembly factor 2
Location	5q12.1
Locus type	gene with protein product
Status	Approved
Aliases	B17.2L, MMTN, mimitin
Ensembl gene	ENSG00000164182
Ensembl biotype	protein_coding
OMIM	609653
Entrez	91942

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000296597, ENST00000502658, ENST00000511107, ENST00000512623, ENST00000677756, ENST00000677932, ENST00000678452, ENST00000907122

RefSeq mRNA: 1 — MANE Select: NM_174889 NM_174889

CCDS: CCDS3979

Canonical transcript exons

ENST00000296597 — 4 exons

Exon	Start	End
ENSE00001178522	60945205	60945382
ENSE00003604109	61073125	61073214
ENSE00003628496	61098992	61099032
ENSE00003686163	61152704	61153026

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 96.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.1277 / max 930.7114, expressed in 1802 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56613	12.8050	1757
56612	10.2904	1758
56614	0.0323	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	96.15	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.31	gold quality
gastrocnemius	UBERON:0001388	95.30	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.30	gold quality
lower esophagus	UBERON:0013473	95.29	gold quality
tibial artery	UBERON:0007610	95.19	gold quality
popliteal artery	UBERON:0002250	95.18	gold quality
muscle of leg	UBERON:0001383	95.17	gold quality
skeletal muscle organ	UBERON:0014892	95.12	gold quality
islet of Langerhans	UBERON:0000006	95.11	gold quality
left coronary artery	UBERON:0001626	94.83	gold quality
heart left ventricle	UBERON:0002084	94.65	gold quality
cortical plate	UBERON:0005343	94.60	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.56	gold quality
right atrium auricular region	UBERON:0006631	94.55	gold quality
nucleus accumbens	UBERON:0001882	94.53	gold quality
heart	UBERON:0000948	94.45	gold quality
ascending aorta	UBERON:0001496	94.38	gold quality
thoracic aorta	UBERON:0001515	94.35	gold quality
mucosa of stomach	UBERON:0001199	94.22	gold quality
hypothalamus	UBERON:0001898	94.21	gold quality
pituitary gland	UBERON:0000007	94.19	gold quality
adenohypophysis	UBERON:0002196	94.18	gold quality
right coronary artery	UBERON:0001625	94.07	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.91	gold quality
esophagus	UBERON:0001043	93.73	gold quality
skeletal muscle tissue	UBERON:0001134	93.71	gold quality
pancreas	UBERON:0001264	93.67	gold quality
anterior cingulate cortex	UBERON:0009835	93.63	gold quality
amygdala	UBERON:0001876	93.59	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.07

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 10)

• the novel gene mimitin is a direct transcriptional target of c-Myc, and is involved in Myc-dependent cell proliferation in esophageal squamous cell carcinoma cells (PMID:15774466)
• B17.2L occurred in a 830 kDa subcomplex specifically in patients with mutations in subunits NDUFV1 and NDUFS4 (PMID:17383918)
• the homozygous substitution in NDUFAF2 is the disease-causing mutation, which results in a complex I deficiency in the fibroblasts (PMID:19384974)
• Within the clinical spectrum of Leigh disease, patients with mutations in NDUFAF2 present with a distinct clinical pattern with predominantly brainstem involvement on MRI (PMID:20571988)
• Mimitin and 14-3-3 protein zeta/delta are potential markers of paclitaxel resistance and prognostic factors in ovarian cancer. (PMID:26033570)
• One patient presented with Leigh syndrome and had a homozygous deletion in the NDUFAF2 gene, while the second patient had a homozygous mutation in the POLG gene, [c.1399G>A; p.Ala467Thr]. (PMID:27344355)
• NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4(-/-) mice and Leigh syndrome patients: A stabilizing role for NDUFAF2. (PMID:32335026)
• Upregulation of NDUFAF2 in Lung Adenocarcinoma Is a Novel Independent Prognostic Biomarker. (PMID:36703939)
• Ndufaf2, a protein in mitochondrial complex I, interacts in vivo with methionine sulfoxide reductases. (PMID:36738241)
• Whole genome sequencing followed by functional analysis of genomic deletion encompassing ERCC8 and NDUFAF2 genes in a non-consanguineous Indian family reveals dysfunctional mitochondrial bioenergetics leading to infant mortality. (PMID:38237647)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufaf2	ENSDARG00000069286
mus_musculus	Ndufaf2	ENSMUSG00000068184
rattus_norvegicus	Ndufaf2	ENSRNOG00000055079
drosophila_melanogaster	CG43346	FBGN0263051
caenorhabditis_elegans		WBGENE00013807

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 2 — Q8N183 (reviewed: Q8N183)

Alternative names: B17.2-like, Mimitin, Myc-induced mitochondrial protein, NDUFA12-like protein

All UniProt accessions (7): A0A0S2Z5U1, A0A7I2V3X5, A0A7I2V4Z7, A0A7I2YQX2, D6RA56, H0YA50, Q8N183

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a molecular chaperone for mitochondrial 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. Is involved in the initial steps of cilia formation, including removal of CP110 from the mother centrioles, docking of membrane vesicles to the mother centrioles, and establishment of the transition zone.

Subunit / interactions. Interacts with ARMC9.

Subcellular location. Mitochondrion.

Tissue specificity. Highly expressed in ESCC cells. Also expressed in heart, skeletal muscle, liver, and in fibroblasts.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 10 (MC1DN10) [MIM:618233] 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. MC1DN10 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Induction. By MYC. Direct transcriptional target of MYC.

Similarity. Belongs to the complex I NDUFA12 subunit family.

RefSeq proteins (1): NP_777549* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007763	NDUFA12	Family
IPR052618	ComplexI_NDUFA12	Family

Pfam: PF05071

UniProt features (8 total): sequence variant 3, transit peptide 1, chain 1, region of interest 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N183-F1	78.98	0.39

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): 134

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-6799198	Complex I biogenesis
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-611105	Respiratory electron transport

MSigDB gene sets: 218 (showing top): GOBP_INSULIN_SECRETION, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_NEGATIVE_REGULATION_OF_PEPTIDE_SECRETION, GOBP_HORMONE_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_PROTEIN_SECRETION, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, WANG_LMO4_TARGETS_DN, GOBP_CILIUM_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION, GOBP_NEGATIVE_REGULATION_OF_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION

GO Biological Process (4): mitochondrial respiratory chain complex I assembly (GO:0032981), cilium assembly (GO:0060271), negative regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0061179), cell projection organization (GO:0030030)

GO Molecular Function (2): protein-containing complex binding (GO:0044877), 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
Respiratory electron transport	1
Metabolism	1
Aerobic respiration and respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
NADH dehydrogenase complex assembly	1
mitochondrial respiratory chain complex assembly	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
insulin secretion involved in cellular response to glucose stimulus	1
negative regulation of insulin secretion	1
negative regulation of response to stimulus	1
regulation of insulin secretion involved in cellular response to glucose stimulus	1
cellular component organization	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

1374 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFAF2	NDUFA12	Q9UI09	963
NDUFAF2	NDUFAF4	Q9P032	892
NDUFAF2	NDUFAF5	Q5TEU4	889
NDUFAF2	NDUFV1	P49821	883
NDUFAF2	FOXRED1	Q96CU9	867
NDUFAF2	NDUFS4	O43181	863
NDUFAF2	NDUFS2	O75306	853
NDUFAF2	NDUFS7	O75251	831
NDUFAF2	NDUFAF6	Q330K2	831
NDUFAF2	NDUFV2	P19404	824
NDUFAF2	NDUFA1	O15239	801
NDUFAF2	NDUFS8	O00217	791
NDUFAF2	NDUFA2	O43678	790
NDUFAF2	NDUFS1	P28331	788
NDUFAF2	NDUFS3	O75489	786

IntAct

106 interactions, top by confidence:

A	B	Type	Score
COQ8A	COQ9	psi-mi:“MI:0914”(association)	0.670
NDUFAF4	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFAF2	NDUFA7	psi-mi:“MI:0915”(physical association)	0.620
SMIM1	NDUFAF2	psi-mi:“MI:0915”(physical association)	0.560
NDUFAF2	LPAR3	psi-mi:“MI:0915”(physical association)	0.560
NDUFAF2	STX8	psi-mi:“MI:0915”(physical association)	0.560
CYB5B	NDUFAF2	psi-mi:“MI:0915”(physical association)	0.560
SEC22B	NDUFAF2	psi-mi:“MI:0915”(physical association)	0.560
LAT	NDUFAF2	psi-mi:“MI:0915”(physical association)	0.560
NDUFAF2	SPG21	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	NDUFAF2	psi-mi:“MI:0915”(physical association)	0.560
TMEM201	NDUFAF2	psi-mi:“MI:0915”(physical association)	0.560
rep	AGPS	psi-mi:“MI:0914”(association)	0.530
NDUFV2	NDUFS8	psi-mi:“MI:0914”(association)	0.530
CBLN4	C1QL1	psi-mi:“MI:0914”(association)	0.530
NDUFA7	NDUFA1	psi-mi:“MI:0914”(association)	0.530
CD53	FAM171A2	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
NDUFAF2	ARMC9	psi-mi:“MI:0915”(physical association)	0.470
NDUFAF2	ARMC9	psi-mi:“MI:2364”(proximity)	0.470
ARMC9	NDUFAF2	psi-mi:“MI:2364”(proximity)	0.470
CHST15	SLC43A3	psi-mi:“MI:0914”(association)	0.350
ATXN3	HLA-A	psi-mi:“MI:0914”(association)	0.350
CBLN4	ADAM11	psi-mi:“MI:0914”(association)	0.350
NMES1	NDUFS8	psi-mi:“MI:0914”(association)	0.350
COQ9	NDUFS8	psi-mi:“MI:0914”(association)	0.350

BioGRID (153): NDUFAF2 (Affinity Capture-MS), NDUFAF2 (Affinity Capture-MS), NDUFAF2 (Affinity Capture-MS), NDUFAF2 (Affinity Capture-MS), NDUFAF2 (Affinity Capture-MS), NDUFAF2 (Affinity Capture-MS), NDUFAF2 (Affinity Capture-MS), NDUFAF2 (Affinity Capture-MS), NDUFAF2 (Proximity Label-MS), NDUFAF2 (Proximity Label-MS), NDUFAF2 (Proximity Label-MS), NDUFAF2 (Proximity Label-MS), NDUFAF2 (Proximity Label-MS), NDUFAF2 (Proximity Label-MS), NDUFAF2 (Affinity Capture-MS)

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: Q32P65, Q59J78, Q6C7L6, Q8N183, Q9N2W7, O97725, Q0MQ85, Q0MQ86, Q0MQ87, Q54MV7, Q6CG53, Q7TMF3, Q9M9M9, Q9UI09

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TFEB	“up-regulates quantity by expression”	NDUFAF2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 95 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
FCERI mediated MAPK activation	5	25.4×	7e-05
Complex I biogenesis	8	19.5×	3e-06
Respiratory electron transport	9	12.6×	7e-06
Aerobic respiration and respiratory electron transport	8	10.4×	5e-05
Transcriptional regulation of granulopoiesis	5	9.2×	2e-03
RAF/MAP kinase cascade	6	5.4×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	8	34.6×	6e-08
proton motive force-driven mitochondrial ATP synthesis	7	22.2×	1e-05
aerobic respiration	7	20.9×	1e-05
positive regulation of miRNA transcription	5	17.5×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	11
Uncertain significance	35
Likely benign	66
Benign	12

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1323336	NM_174889.5(NDUFAF2):c.184del (p.Tyr62fs)	Pathogenic
1595	NM_174889.5(NDUFAF2):c.103del (p.Ile35fs)	Pathogenic
1696036	NC_000005.9:g.(60241210_60368951)(60448865?)del	Pathogenic
214743	NM_174889.5(NDUFAF2):c.386_390del (p.Ile129fs)	Pathogenic
2427520	NC_000005.9:g.(?60394799)(60394879_?)del	Pathogenic
2755333	NM_174889.5(NDUFAF2):c.174dup (p.Glu59fs)	Pathogenic
2759897	NM_174889.5(NDUFAF2):c.192_193del (p.Asp66fs)	Pathogenic
2975537	NM_174889.5(NDUFAF2):c.192del (p.Asp66fs)	Pathogenic
3062814	GRCh37/hg19 5q12.1(chr5:60276865-60467589)x1	Pathogenic
3246570	NC_000005.9:g.(?60368932)(60394879_?)del	Pathogenic
3246571	NC_000005.9:g.(?60368932)(60448782_?)del	Pathogenic
4847484	NC_000005.9:g.(?60241031)(60369042_60394818)del	Pathogenic
496598	NM_174889.5(NDUFAF2):c.9G>A (p.Trp3Ter)	Pathogenic
984515	NM_174889.5(NDUFAF2):c.130_131del (p.Gln44fs)	Pathogenic
1328105	GRCh37/hg19 5q12.1(chr5:60268673-60374105)x0	Likely pathogenic
1696037	NC_000005.9:g.(?60240955)(60241210_60368951)del	Likely pathogenic
2429317	NM_174889.5(NDUFAF2):c.9_10del (p.Trp3fs)	Likely pathogenic
2731416	NM_174889.5(NDUFAF2):c.128-4_128-2del	Likely pathogenic
3246572	NC_000005.9:g.(?60368932)(60394879_?)dup	Likely pathogenic
3592732	NM_174889.5(NDUFAF2):c.167del (p.Asn56fs)	Likely pathogenic
3592733	NM_174889.5(NDUFAF2):c.265_268del (p.Leu89fs)	Likely pathogenic
3592734	NM_174889.5(NDUFAF2):c.289G>T (p.Glu97Ter)	Likely pathogenic
3592735	NM_174889.5(NDUFAF2):c.304del (p.Ser102fs)	Likely pathogenic
3592737	NM_174889.5(NDUFAF2):c.330dup (p.Leu111fs)	Likely pathogenic
488707	NM_174889.5(NDUFAF2):c.79C>T (p.Gln27Ter)	Likely pathogenic

SpliceAI

2173 predictions. Top by Δscore:

Variant	Effect	Δscore
5:61073122:TAG:T	acceptor_loss	1.0000
5:61073123:A:AG	acceptor_gain	1.0000
5:61073123:A:G	acceptor_loss	1.0000
5:61073123:AG:A	acceptor_gain	1.0000
5:61073124:G:GA	acceptor_gain	1.0000
5:61073124:GG:G	acceptor_gain	1.0000
5:61073124:GGA:G	acceptor_gain	1.0000
5:61073124:GGAC:G	acceptor_gain	1.0000
5:61073124:GGACA:G	acceptor_gain	1.0000
5:61073210:GGAAG:G	donor_gain	1.0000
5:61073211:GAAG:G	donor_gain	1.0000
5:61073211:GAAGG:G	donor_gain	1.0000
5:61073212:AAGG:A	donor_gain	1.0000
5:61073213:AGG:A	donor_loss	1.0000
5:61073213:AGGTA:A	donor_gain	1.0000
5:61073214:GGT:G	donor_gain	1.0000
5:61073215:G:GA	donor_loss	1.0000
5:61073215:G:GG	donor_gain	1.0000
5:61073215:GTAAG:G	donor_gain	1.0000
5:61073216:TAAGT:T	donor_gain	1.0000
5:61098027:GC:G	donor_gain	1.0000
5:61098990:A:AG	acceptor_gain	1.0000
5:61098990:A:AT	acceptor_loss	1.0000
5:61098990:AGCTT:A	acceptor_gain	1.0000
5:61098991:G:GA	acceptor_gain	1.0000
5:61098991:GC:G	acceptor_gain	1.0000
5:61098991:GCTT:G	acceptor_gain	1.0000
5:61098991:GCTTG:G	acceptor_gain	1.0000
5:60945307:G:T	donor_gain	0.9900
5:60945380:GAG:G	donor_gain	0.9900

AlphaMissense

1114 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:61073208:T:A	W71R	0.993
5:61073208:T:C	W71R	0.993
5:61098994:T:A	W74R	0.993
5:61098994:T:C	W74R	0.993
5:61073210:G:C	W71C	0.986
5:61073210:G:T	W71C	0.986
5:61098996:G:C	W74C	0.982
5:61098996:G:T	W74C	0.982
5:61073209:G:C	W71S	0.973
5:61073214:G:C	A73P	0.972
5:61152905:T:C	F154L	0.970
5:61152907:T:A	F154L	0.970
5:61152907:T:G	F154L	0.970
5:61098995:G:C	W74S	0.964
5:60945349:T:C	Y32H	0.959
5:60945349:T:G	Y32D	0.953
5:60945350:A:C	Y32S	0.953
5:61073147:A:C	R50S	0.952
5:61073147:A:T	R50S	0.952
5:61098994:T:G	W74G	0.949
5:61152920:T:A	W159R	0.948
5:61152920:T:C	W159R	0.948
5:61098995:G:T	W74L	0.944
5:61152922:G:C	W159C	0.943
5:61152922:G:T	W159C	0.943
5:61099022:C:A	P83H	0.941
5:61073209:G:T	W71L	0.936
5:60945333:C:A	D26E	0.927
5:60945333:C:G	D26E	0.927
5:60945331:G:C	D26H	0.919

dbSNP variants (sampled 300 via entrez): RS1000001422 (5:61072565 G>A), RS1000016260 (5:61000253 G>T), RS1000031886 (5:60991248 G>T), RS1000050628 (5:61093342 C>A), RS1000052400 (5:60945024 C>A,T), RS1000076870 (5:61129212 A>G), RS1000105125 (5:61036990 AT>A), RS1000118392 (5:60967597 T>G), RS1000146769 (5:60984577 T>C), RS1000152289 (5:60952980 A>G), RS1000157862 (5:60985464 C>G), RS1000161091 (5:60996372 T>C), RS1000166445 (5:61111875 C>A,G), RS1000169102 (5:61041697 A>G,T), RS1000174723 (5:60962682 A>C)

Disease associations

OMIM: gene MIM:609653 | disease phenotypes: MIM:256000, MIM:618233, MIM:252010

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 10	Strong	Autosomal recessive
Leigh syndrome	Strong	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	Definitive	AR
mitochondrial disease	Definitive	AR

Mondo (5): Leigh syndrome (MONDO:0009723), mitochondrial complex I deficiency, nuclear type 10 (MONDO:0032616), 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

53 total (30 of 53 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:0000544	External ophthalmoplegia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000666	Horizontal 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:0001265	Hyporeflexia
HP:0001284	Areflexia
HP:0001298	Encephalopathy
HP:0001310	Dysmetria
HP:0001324	Muscle weakness
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001639	Hypertrophic cardiomyopathy
HP:0001943	Hypoglycemia
HP:0002013	Vomiting

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST003984_25	Parkinson’s disease	1.000000e-08
GCST004521_137	Autism spectrum disorder or schizophrenia	2.000000e-09
GCST004521_26	Autism spectrum disorder or schizophrenia	1.000000e-09
GCST004521_260	Autism spectrum disorder or schizophrenia	6.000000e-09
GCST005316_578	Intelligence (MTAG)	2.000000e-12
GCST008595_159	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	2.000000e-15
GCST009523_27	Household income	2.000000e-08
GCST009524_16	Household income (MTAG)	1.000000e-09
GCST009524_226	Household income (MTAG)	4.000000e-20
GCST009524_250	Household income (MTAG)	2.000000e-11
GCST010701_32	Cortical surface area (MOSTest)	2.000000e-29
GCST010702_115	Subcortical volume (MOSTest)	2.000000e-09
GCST010703_98	Brain morphology (MOSTest)	5.000000e-41
GCST011616_59	Cortical volume	3.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0009695	household income
EFO:0004346	neuroimaging measurement

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 (2): CHEMBL2363065 (PROTEIN COMPLEX), CHEMBL6067536 (SINGLE PROTEIN)

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

ChEMBL bioactivities

8 potent at pChembl≥5 of 20 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 30 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

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	affects cotreatment, increases expression, decreases expression	2
Tretinoin	decreases expression	2
Tunicamycin	increases expression	2
bisphenol A	affects expression	1
arsenite	affects binding, increases reaction	1
methylparaben	decreases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
aflatoxin B2	decreases methylation	1
chloropicrin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
Rosiglitazone	increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Glyphosate	affects methylation	1
Ethanol	affects cotreatment, decreases expression, increases abundance	1
Arsenic	increases abundance, increases expression, affects cotreatment	1
Atrazine	increases expression	1
Gasoline	increases abundance, affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Manganese	increases expression, affects cotreatment, increases abundance	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Silicon Dioxide	increases methylation	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases 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

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1P1	Abcam K-562 NDUFAF2 KO	Cancer cell line	Female
CVCL_D2KL	Abcam Raji NDUFAF2 KO	Cancer cell line	Male
CVCL_E2D7	HAP1 NDUFAF2 (-) 1	Cancer cell line	Male
CVCL_E2D8	HAP1 NDUFAF2 (-) 2	Cancer cell line	Male
CVCL_WQ03	Abcam Jurkat NDUFAF2 KO	Cancer 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