NDUFA2

Summary

NDUFA2 (NADH:ubiquinone oxidoreductase subunit A2, HGNC:7685) is a protein-coding gene on chromosome 5q31.3, encoding NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 (O43678). 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: 43.1% of cell lines).

The encoded protein is a subunit of the hydrophobic protein fraction of the NADH:ubiquinone oxidoreductase (complex 1), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane, and may be involved in regulating complex I activity or its assembly via assistance in redox processes. Mutations in this gene are associated with Leigh syndrome, an early-onset progressive neurodegenerative disorder. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 4695 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 84 total — 3 pathogenic
• Phenotypes (HPO): 31
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 43.1% of screened cell lines
• MANE Select transcript: NM_002488

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7685
Approved symbol	NDUFA2
Name	NADH:ubiquinone oxidoreductase subunit A2
Location	5q31.3
Locus type	gene with protein product
Status	Approved
Aliases	B8
Ensembl gene	ENSG00000131495
Ensembl biotype	protein_coding
OMIM	602137
Entrez	4695

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000252102, ENST00000502960, ENST00000510680, ENST00000512088

RefSeq mRNA: 2 — MANE Select: NM_002488 NM_001185012, NM_002488

CCDS: CCDS4234, CCDS54911

Canonical transcript exons

ENST00000252102 — 3 exons

Exon	Start	End
ENSE00000765411	140647256	140647362
ENSE00001216133	140647483	140647630
ENSE00002046535	140645285	140645678

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 98.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 79.8609 / max 334.5012, expressed in 1824 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63823	75.5414	1824
63825	2.2834	1060
63824	1.7505	1202
63822	0.2856	138

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
biceps brachii	UBERON:0001507	98.91	gold quality
heart right ventricle	UBERON:0002080	98.86	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.79	gold quality
adult organism	UBERON:0007023	98.66	gold quality
triceps brachii	UBERON:0001509	98.63	gold quality
apex of heart	UBERON:0002098	98.63	gold quality
mucosa of transverse colon	UBERON:0004991	98.58	gold quality
vastus lateralis	UBERON:0001379	98.49	gold quality
quadriceps femoris	UBERON:0001377	98.39	gold quality
diaphragm	UBERON:0001103	98.38	gold quality
cardiac ventricle	UBERON:0002082	98.36	gold quality
heart left ventricle	UBERON:0002084	98.35	gold quality
body of tongue	UBERON:0011876	98.34	gold quality
right adrenal gland	UBERON:0001233	98.33	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.33	gold quality
left adrenal gland cortex	UBERON:0035825	98.31	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.29	gold quality
left adrenal gland	UBERON:0001234	98.26	gold quality
gluteal muscle	UBERON:0002000	98.25	gold quality
adrenal cortex	UBERON:0001235	98.22	gold quality
right adrenal gland cortex	UBERON:0035827	98.13	gold quality
gastrocnemius	UBERON:0001388	98.11	gold quality
trabecular bone tissue	UBERON:0002483	98.05	gold quality
adult mammalian kidney	UBERON:0000082	98.04	gold quality
right atrium auricular region	UBERON:0006631	97.98	gold quality
heart	UBERON:0000948	97.95	gold quality
prefrontal cortex	UBERON:0000451	97.92	gold quality
colonic mucosa	UBERON:0000317	97.89	gold quality
cardiac atrium	UBERON:0002081	97.89	gold quality
muscle organ	UBERON:0001630	97.87	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting NDUFA2, 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-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-4774-3P	98.90	67.82	737
HSA-MIR-6873-5P	98.45	66.14	1417
HSA-MIR-3132	97.96	67.91	711
HSA-MIR-3620-3P	97.78	64.88	772
HSA-MIR-3936	97.64	64.47	732
HSA-MIR-197-5P	97.23	68.10	596
HSA-MIR-6836-3P	97.08	64.99	712
HSA-MIR-3152-5P	96.98	66.88	819

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 43.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 3)

• solution structure shows a thioredoxin fold with highest similarities to the human thioredoxin mutant C73S and thioredoxin 2 from Anabeana sp (PMID:15341729)
• A novel mechanism of lipoteichoic acid (LTA)-induced cytokine induction in human peripheral blood cells involves uptake of LTA and subsequent intracellular recognition driven by Toll-like receptor (TLR)2, TLR6, and CD14. (PMID:20713893)
• Review of a biorepository of patients with unsolved genetic leukoencephalopathies who underwent whole-exome or genome sequencing allowed us to identify a second patient with compound heterozygous mutations in NDUFA2. Only 1 other patient with mutations in NDUFA2 and a different phenotype (Leigh syndrome) has previously been reported. This is the first report of cystic leukoencephalopathy caused by mutations in NDUFA2. (PMID:28857146)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufa2	ENSDARG00000021984
mus_musculus	Ndufa2	ENSMUSG00000014294
rattus_norvegicus	Ndufa2	ENSRNOG00000017571
rattus_norvegicus	LOC120099907	ENSRNOG00000043512
drosophila_melanogaster	ND-B8	FBGN0040705
caenorhabditis_elegans	ndua-2	WBGENE00013406

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 — O43678 (reviewed: O43678)

Alternative names: Complex I-B8, NADH-ubiquinone oxidoreductase B8 subunit

All UniProt accessions (1): O43678

UniProt curated annotations — full annotation on UniProt →

Function. Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone.

Subunit / interactions. Complex I is composed of 45 different subunits.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 13 (MC1DN13) [MIM:618235] 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. MC1DN13 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 NDUFA2 subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
O43678-1	1	yes
O43678-2	2

RefSeq proteins (2): NP_001171941, NP_002479* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007741	Ribosomal_mL43/mS25/NADH_DH	Domain
IPR016464	NADH_Ub_cplx-1_asu_su-2	Family
IPR036249	Thioredoxin-like_sf	Homologous_superfamily

Pfam: PF05047

UniProt features (19 total): strand 7, helix 4, modified residue 3, initiator methionine 1, chain 1, disulfide bond 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

8 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
1S3A	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43678-F1	86.11	0.65

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): 2, 64, 64

Disulfide bonds (1): 24–58

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-611105	Respiratory electron transport
R-HSA-6799198	Complex I biogenesis
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 308 (showing top): MODULE_93, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, MORF_MBD4, MODULE_77, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, MARTINEZ_RB1_TARGETS_UP, MORF_SKP1A, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT

GO Biological Process (5): blastocyst hatching (GO:0001835), mitochondrial electron transport, NADH to ubiquinone (GO:0006120), aerobic respiration (GO:0009060), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), proton transmembrane transport (GO:1902600)

GO Molecular Function (1): NADH dehydrogenase (ubiquinone) activity (GO:0008137)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial membrane (GO:0031966), respiratory chain complex I (GO:0045271), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Respiratory electron transport	1
Metabolism of proteins	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	2
blastocyst development	1
hatching	1
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
cellular respiration	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
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrial envelope	1
organelle membrane	1
NADH dehydrogenase complex	1
respiratory chain complex	1
transmembrane transporter complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2918 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFA2	NDUFS1	P28331	989
NDUFA2	NDUFV2	P19404	985
NDUFA2	NDUFV1	P49821	981
NDUFA2	NDUFA7	O95182	965
NDUFA2	COXFA4	O00483	963
NDUFA2	NDUFS6	O75380	949
NDUFA2	NDUFA10	O95299	947
NDUFA2	NDUFB7	P17568	940
NDUFA2	NDUFA3	O95167	937
NDUFA2	NDUFAB1	O14561	934
NDUFA2	NDUFC2	O95298	929
NDUFA2	NDUFA9	Q16795	926
NDUFA2	NDUFA5	Q16718	921
NDUFA2	NDUFB3	O43676	920
NDUFA2	NDUFB1	O75438	920

IntAct

122 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
EXOC1	EXOC5	psi-mi:“MI:0914”(association)	0.730
NDUFS6	NDUFS8	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
NDUFS5	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFA9	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFV2	NDUFS8	psi-mi:“MI:0914”(association)	0.530
PML	NDUFA2	psi-mi:“MI:0914”(association)	0.530
DNAJC30	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFC2	NDUFS4	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
PRRT2	NDUFS4	psi-mi:“MI:0914”(association)	0.530
HTRA2	HAX1	psi-mi:“MI:2364”(proximity)	0.420
NDUFA2	NDUFS8	psi-mi:“MI:0915”(physical association)	0.400
	FER1L5	psi-mi:“MI:0915”(physical association)	0.400
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (264): NDUFA2 (Affinity Capture-MS), NDUFA2 (Affinity Capture-MS), NDUFA2 (Affinity Capture-MS), NDUFA2 (Affinity Capture-MS), NDUFA2 (Affinity Capture-MS), ATP6V0D1 (Co-fractionation), NDUFA2 (Co-fractionation), NDUFA2 (Co-fractionation), NDUFA2 (Co-fractionation), NDUFA2 (Co-fractionation), NDUFA2 (Co-fractionation), NDUFA2 (Co-fractionation), NDUFA2 (Co-fractionation), NDUFA2 (Co-fractionation), NDUFA2 (Co-fractionation)

ESM2 similar proteins: A4II73, A8WH18, B0VXH3, B1MT69, B2B9A1, B5X5B4, B9SEZ6, D0EYG3, O19097, O43678, O43837, P0CB79, P0CB80, P13621, P48047, P63300, P63301, P63302, P63303, P99029, Q02370, Q06647, Q07842, Q0MQ92, Q24439, Q28479, Q3UQA7, Q4R5E2, Q4R5Y4, Q568W0, Q5BK18, Q5NVB2, Q5ZJN8, Q68FX0, Q6GP98, Q6PBD1, Q6PBM1, Q6ZJS7, Q7S300, Q7SGH0

Diamond homologs: O43678, P0CB79, P0CB80, Q02370, Q07842, Q0MQ92, Q4R5E2, Q9CQ75, Q9FIJ2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NDUFA2	“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 115 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	22	47.9×	5e-30
Respiratory electron transport	21	26.3×	1e-22
Aerobic respiration and respiratory electron transport	21	24.5×	3e-22
Mitochondrial protein degradation	9	13.5×	9e-07

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	17	61.6×	1e-24
proton motive force-driven mitochondrial ATP synthesis	21	55.9×	3e-29
aerobic respiration	20	50.1×	7e-27
mitochondrial respiratory chain complex I assembly	10	41.5×	5e-12
cell fate commitment	5	14.9×	2e-03
cellular response to retinoic acid	5	11.8×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	39
Likely benign	26
Benign	8

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
214711	NM_002488.5(NDUFA2):c.134A>C (p.Lys45Thr)	Pathogenic
7515	NM_002488.5(NDUFA2):c.208+5G>A	Pathogenic
978071	NM_002488.5(NDUFA2):c.170A>C (p.Glu57Ala)	Pathogenic

SpliceAI

2943 predictions. Top by Δscore:

Variant	Effect	Δscore
5:140639807:G:GT	donor_gain	1.0000
5:140639820:G:T	donor_gain	1.0000
5:140641650:T:A	acceptor_gain	1.0000
5:140641655:T:TA	acceptor_gain	1.0000
5:140641658:A:AG	acceptor_gain	1.0000
5:140641660:TCCA:T	acceptor_loss	1.0000
5:140641661:CCAG:C	acceptor_loss	1.0000
5:140641663:A:AG	acceptor_gain	1.0000
5:140641664:G:GA	acceptor_loss	1.0000
5:140641664:G:GG	acceptor_gain	1.0000
5:140641664:GGT:G	acceptor_gain	1.0000
5:140641777:TCCGG:T	donor_loss	1.0000
5:140641781:G:GG	donor_gain	1.0000
5:140642054:G:GG	donor_gain	1.0000
5:140642584:A:AG	acceptor_gain	1.0000
5:140642585:G:GA	acceptor_gain	1.0000
5:140642672:G:GG	donor_gain	1.0000
5:140643778:AGCT:A	acceptor_gain	1.0000
5:140643779:GCTG:G	acceptor_gain	1.0000
5:140639579:GAGC:G	donor_gain	0.9900
5:140639582:C:G	donor_gain	0.9900
5:140639599:G:GT	donor_gain	0.9900
5:140639628:G:GT	donor_gain	0.9900
5:140639820:G:GT	donor_gain	0.9900
5:140640840:T:G	donor_gain	0.9900
5:140641115:G:T	donor_gain	0.9900
5:140641650:T:TA	acceptor_loss	0.9900
5:140641659:C:G	acceptor_gain	0.9900
5:140641663:AG:A	acceptor_gain	0.9900
5:140641663:AGGT:A	acceptor_gain	0.9900

AlphaMissense

636 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:140647329:C:A	K45N	0.985
5:140647329:C:G	K45N	0.985
5:140647297:C:G	R56P	0.980
5:140647362:C:A	R34S	0.980
5:140647362:C:G	R34S	0.980
5:140647526:G:T	R20S	0.980
5:140647483:C:A	R34M	0.979
5:140647261:C:G	R68P	0.977
5:140647298:G:T	R56S	0.976
5:140647303:A:G	L54P	0.976
5:140647494:G:C	S30R	0.976
5:140647494:G:T	S30R	0.976
5:140647496:T:G	S30R	0.976
5:140647270:A:G	L65P	0.972
5:140647532:C:T	E18K	0.972
5:140647270:A:T	L65H	0.971
5:140647483:C:G	R34T	0.971
5:140647300:A:T	I55N	0.969
5:140645651:A:C	L79W	0.968
5:140647264:G:T	A67D	0.968
5:140647356:G:C	F36L	0.968
5:140647356:G:T	F36L	0.968
5:140647358:A:G	F36L	0.968
5:140647306:A:T	I53N	0.966
5:140645672:C:T	G72D	0.962
5:140647290:G:C	C58W	0.960
5:140647306:A:C	I53S	0.960
5:140645627:A:T	V87E	0.959
5:140647357:A:G	F36S	0.959
5:140647522:A:T	I21N	0.959

dbSNP variants (sampled 300 via entrez): RS1000065251 (5:140648011 T>G), RS1000671031 (5:140649359 C>T), RS1000938011 (5:140649531 A>C), RS1000986821 (5:140647457 G>A,C,T), RS1001122884 (5:140648360 C>A,T), RS1001198011 (5:140648654 C>A), RS1002752155 (5:140649083 C>G,T), RS1003417558 (5:140646507 G>A), RS1003426022 (5:140645234 C>T), RS1003805017 (5:140647733 T>A,C,G), RS10042624 (5:140649200 T>C), RS10042625 (5:140649205 T>C), RS1005022786 (5:140648735 T>G), RS1005899251 (5:140645832 A>G), RS1006795026 (5:140649560 T>G)

Disease associations

OMIM: gene MIM:602137 | disease phenotypes: MIM:252010, MIM:618235

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 13	Strong	Autosomal recessive
Leigh syndrome	Moderate	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive
cystic leukoencephalopathy without megalencephaly	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): mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224), mitochondrial complex I deficiency, nuclear type 13 (MONDO:0032618), Leigh syndrome (MONDO:0009723), (MONDO:0016815), cystic leukoencephalopathy without megalencephaly (MONDO:0013058)

Orphanet (0):

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000737	Irritability
HP:0001249	Intellectual disability
HP:0001257	Spasticity
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001298	Encephalopathy
HP:0001508	Failure to thrive
HP:0001522	Death in infancy
HP:0001639	Hypertrophic cardiomyopathy
HP:0001662	Bradycardia
HP:0001695	Cardiac arrest
HP:0001941	Acidosis
HP:0001942	Metabolic acidosis
HP:0001945	Fever
HP:0002013	Vomiting
HP:0002059	Cerebral atrophy
HP:0002069	Bilateral tonic-clonic seizure
HP:0002079	Hypoplasia of the corpus callosum
HP:0002104	Apnea
HP:0002240	Hepatomegaly
HP:0002376	Developmental regression
HP:0003234	Decreased circulating carnitine concentration
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0007325	Generalized dystonia
HP:0011153	Focal motor seizure
HP:0011923	Decreased activity of mitochondrial complex I
HP:0011968	Feeding difficulties

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004946_157	Schizophrenia	2.000000e-08
GCST006803_54	Schizophrenia	8.000000e-07
GCST009523_35	Household income	1.000000e-08
GCST010146_22	Serum immune biomarker levels	7.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009695	household income
EFO:0004872	inflammatory biomarker 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
C567845	Leukoencephalopathy, Cystic, Without Megalencephaly (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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
bisphenol A	affects expression, increases expression	2
Acetaminophen	increases expression	2
Vehicle Emissions	decreases expression, decreases reaction	2
Doxorubicin	affects expression	2
Cyclosporine	decreases expression	2
Particulate Matter	increases abundance, decreases expression, decreases reaction	2
aristolochic acid I	increases expression	1
dicrotophos	decreases 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
trichostatin A	affects expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	decreases expression	1
ochratoxin A	decreases expression	1
3-methyladenine	decreases expression, decreases reaction, increases reaction	1
acipimox	increases expression	1
1-nitropyrene	decreases expression, decreases reaction, increases expression, increases reaction	1
phenethyl isothiocyanate	affects binding	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
corosolic acid	decreases expression	1
K 7174	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
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
MRK 003	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2353025	Binding	Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation at 30 uM incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	Semisynthetic studies identify mitochondria poisons from botanical dietary supplements–geranyloxycoumarins from Aegle marmelos. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1YD	Abcam HeLa NDUFA2 KO	Cancer cell line	Female
CVCL_TA12	HAP1 NDUFA2 (-) 1	Cancer cell line	Male
CVCL_TA13	HAP1 NDUFA2 (-) 2	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