NDUFS2

Summary

NDUFS2 (NADH:ubiquinone oxidoreductase core subunit S2, HGNC:7708) is a protein-coding gene on chromosome 1q23.3, encoding NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial (O75306). 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: 40.6% of cell lines).

The protein encoded by this gene is a core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Mammalian mitochondrial complex I is composed of at least 43 different subunits, 7 of which are encoded by the mitochondrial genome, and the rest are the products of nuclear genes. The iron-sulfur protein fraction of complex I is made up of 7 subunits, including this gene product. Complex I catalyzes the NADH oxidation with concomitant ubiquinone reduction and proton ejection out of the mitochondria. Mutations in this gene are associated with mitochondrial complex I deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4720 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 266 total — 6 pathogenic, 5 likely-pathogenic
• GTEx eGene: eQTL in 38 tissues, sQTL in 28 (q < 0.05)
• Phenotypes (HPO): 78
• Cancer dependency (DepMap): dependent in 40.6% of screened cell lines
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.69 (unconstrained)
• MANE Select transcript: NM_001377299
• Interaction hub: 2,917 STRING partners (top 3% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7708
Approved symbol	NDUFS2
Name	NADH:ubiquinone oxidoreductase core subunit S2
Location	1q23.3
Locus type	gene with protein product
Status	Approved
Aliases	CI-49
Ensembl gene	ENSG00000158864
Ensembl biotype	protein_coding
OMIM	602985
Entrez	4720

Gene structure

Transcript identifiers

Ensembl transcripts: 113 — 41 nonsense_mediated_decay, 40 retained_intron, 20 protein_coding, 12 protein_coding_CDS_not_defined

MANE Select: ENST00000676972

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 5, TSL 3: 5, TSL 5: 3

ENST00000676972, ENST00000367993, ENST00000392179, ENST00000465923, ENST00000467295, ENST00000468828, ENST00000473321, ENST00000475570, ENST00000478866, ENST00000479948, ENST00000480762, ENST00000483804, ENST00000492153, ENST00000493849, ENST00000496133, ENST00000496553, ENST00000676535, ENST00000676583, ENST00000676600, ENST00000676653, ENST00000676726, ENST00000676770, ENST00000676795, ENST00000676871, ENST00000676991, ENST00000677033, ENST00000677045, ENST00000677050, ENST00000677063, ENST00000677081, ENST00000677089, ENST00000677103, ENST00000677138, ENST00000677178, ENST00000677231, ENST00000677336, ENST00000677350, ENST00000677358, ENST00000677383, ENST00000677453, ENST00000677457, ENST00000677471, ENST00000677495, ENST00000677547, ENST00000677550, ENST00000677577, ENST00000677579, ENST00000677613, ENST00000677643, ENST00000677653, ENST00000677657, ENST00000677736, ENST00000677745, ENST00000677807, ENST00000677809, ENST00000677837, ENST00000677846, ENST00000677916, ENST00000677925, ENST00000677948, ENST00000678052, ENST00000678068, ENST00000678130, ENST00000678328, ENST00000678356, ENST00000678484, ENST00000678492, ENST00000678507, ENST00000678511, ENST00000678532, ENST00000678559, ENST00000678605, ENST00000678613, ENST00000678648, ENST00000678783, ENST00000678793, ENST00000678850, ENST00000678880, ENST00000678911, ENST00000678966, ENST00000678982, ENST00000679064, ENST00000679071, ENST00000679142, ENST00000679169, ENST00000679176, ENST00000679215, ENST00000679218, ENST00000679239, ENST00000679282, ENST00000873085, ENST00000960014, ENST00000960015, ENST00001000175, ENST00001000176, ENST00001047071, ENST00001047072, ENST00001047073, ENST00001047074, ENST00001047075, ENST00001047076, ENST00001047078, ENST00001047079, ENST00001047080, ENST00001047081, ENST00001047083, ENST00001047087, ENST00001047088, ENST00001077084, ENST00001077085, ENST00001077088, ENST00001098883, ENST00001143827

RefSeq mRNA: 8 — MANE Select: NM_001377299 NM_001166159, NM_001377298, NM_001377299, NM_001377300, NM_001377301, NM_001377302, NM_001410889, NM_004550

CCDS: CCDS1224, CCDS53404, CCDS91086

Canonical transcript exons

ENST00000676972 — 14 exons

Exon	Start	End
ENSE00001884216	161214156	161214395
ENSE00003464463	161203437	161203543
ENSE00003465746	161213649	161213732
ENSE00003466143	161210111	161210188
ENSE00003471424	161213864	161213921
ENSE00003489152	161206407	161206597
ENSE00003495523	161209857	161209931
ENSE00003541082	161213380	161213475
ENSE00003550227	161209193	161209313
ENSE00003567087	161212351	161212480
ENSE00003587080	161210591	161210710
ENSE00003634980	161210304	161210389
ENSE00003672735	161209483	161209595
ENSE00003906071	161202367	161202480

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 75.9535 / max 561.1559, expressed in 1824 samples.

Highest expression (Bgee): apex of heart, gastrocnemius, heart left ventricle, cardiac ventricle, mucosa of transverse colon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

NDUFS2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 38 tissues and its splicing (sQTL) in 28 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 66 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Sun Exposed Lower leg	sqtl	4.1e-52	-0.63	1:161210087:G:A
Skin Not Sun Exposed Suprapubic	sqtl	4.8e-44	-0.60	1:161210087:G:A
Adipose Subcutaneous	sqtl	2.1e-39	-0.51	1:161210087:G:A
Muscle Skeletal	sqtl	7.7e-35	-0.48	1:161210087:G:A
Breast Mammary Tissue	sqtl	1.4e-30	-0.74	1:161210087:G:A
Artery Tibial	sqtl	1.4e-23	-0.35	1:161210087:G:A
Lung	sqtl	3.7e-22	-0.41	1:161210087:G:A
Nerve Tibial	sqtl	9.3e-22	-0.32	1:161210087:G:A
Skin Not Sun Exposed Suprapubic	eqtl	3.5e-15	-0.26	1:161210087:G:A
Esophagus Muscularis	sqtl	1.9e-14	-0.46	1:161210087:G:A
Nerve Tibial	eqtl	1.8e-13	-0.21	1:161216523:C:T
Testis	eqtl	8.4e-13	-0.25	1:161210087:G:A
Artery Aorta	sqtl	1.6e-12	-0.48	1:161210087:G:A
Adipose Visceral Omentum	sqtl	6.4e-12	-0.29	1:161210087:G:A
Brain Cerebellum	eqtl	1.1e-11	-0.46	1:161196933:G:T
Cells Cultured fibroblasts	eqtl	1.1e-11	+0.15	1:161198214:C:T
Brain Frontal Cortex BA9	eqtl	3.1e-11	+0.31	1:161214307:A:G
Brain Cerebellar Hemisphere	eqtl	7.5e-10	-0.36	1:161196933:G:T
Skin Sun Exposed Lower leg	eqtl	8.4e-10	-0.17	1:161210087:G:A
Esophagus Muscularis	eqtl	1.6e-09	-0.34	1:161196933:G:T

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
6217	75.4756	1824
6216	0.4779	298

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.19	gold quality
gastrocnemius	UBERON:0001388	99.01	gold quality
heart left ventricle	UBERON:0002084	98.98	gold quality
cardiac ventricle	UBERON:0002082	98.96	gold quality
mucosa of transverse colon	UBERON:0004991	98.84	gold quality
muscle of leg	UBERON:0001383	98.81	gold quality
right adrenal gland	UBERON:0001233	98.75	gold quality
heart right ventricle	UBERON:0002080	98.70	gold quality
right adrenal gland cortex	UBERON:0035827	98.70	gold quality
right atrium auricular region	UBERON:0006631	98.69	gold quality
left ventricle myocardium	UBERON:0006566	98.66	gold quality
muscle organ	UBERON:0001630	98.62	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.60	gold quality
cardiac atrium	UBERON:0002081	98.59	gold quality
left adrenal gland	UBERON:0001234	98.51	gold quality
heart	UBERON:0000948	98.47	gold quality
body of tongue	UBERON:0011876	98.37	gold quality
left adrenal gland cortex	UBERON:0035825	98.36	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.30	gold quality
diaphragm	UBERON:0001103	98.24	gold quality
skeletal muscle tissue	UBERON:0001134	98.21	gold quality
adrenal cortex	UBERON:0001235	98.20	gold quality
vastus lateralis	UBERON:0001379	98.20	gold quality
deltoid	UBERON:0001476	98.17	gold quality
left ovary	UBERON:0002119	98.15	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.15	gold quality
transverse colon	UBERON:0001157	98.14	gold quality
quadriceps femoris	UBERON:0001377	98.12	gold quality
adrenal gland	UBERON:0002369	98.10	gold quality
right ovary	UBERON:0002118	98.09	gold quality
cerebellar hemisphere	UBERON:0002245	98.08	gold quality
triceps brachii	UBERON:0001509	98.06	gold quality
right lobe of liver	UBERON:0001114	98.05	gold quality
cerebellar cortex	UBERON:0002129	98.05	gold quality
adult mammalian kidney	UBERON:0000082	98.04	gold quality
rectum	UBERON:0001052	98.03	gold quality
muscle tissue	UBERON:0002385	98.03	gold quality
body of stomach	UBERON:0001161	97.96	gold quality
metanephros cortex	UBERON:0010533	97.96	gold quality
right frontal lobe	UBERON:0002810	97.90	gold quality
myocardium	UBERON:0002349	97.81	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.78	gold quality
biceps brachii	UBERON:0001507	97.75	gold quality
prefrontal cortex	UBERON:0000451	97.65	gold quality
cerebellum	UBERON:0002037	97.59	gold quality
tibialis anterior	UBERON:0001385	97.58	gold quality
lower esophagus	UBERON:0013473	97.54	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.54	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.51	gold quality
colon	UBERON:0001155	97.46	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.46	gold quality
large intestine	UBERON:0000059	97.45	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.44	gold quality
renal medulla	UBERON:0000362	97.43	gold quality
lower esophagus mucosa	UBERON:0035834	97.39	gold quality
stromal cell of endometrium	CL:0002255	97.38	gold quality
gluteal muscle	UBERON:0002000	97.38	gold quality
sigmoid colon	UBERON:0001159	97.33	gold quality
intestine	UBERON:0000160	97.26	gold quality
skin of leg	UBERON:0001511	97.26	gold quality
esophagus	UBERON:0001043	97.25	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.25	gold quality
esophagus squamous epithelium	UBERON:0006920	97.21	gold quality
liver	UBERON:0002107	97.20	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.19	gold quality
skin of abdomen	UBERON:0001416	97.17	gold quality
small intestine	UBERON:0002108	97.17	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.17	gold quality
left uterine tube	UBERON:0001303	97.14	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.13	gold quality
stomach	UBERON:0000945	97.12	gold quality
nucleus accumbens	UBERON:0001882	97.11	gold quality
esophagus mucosa	UBERON:0002469	97.10	gold quality
kidney	UBERON:0002113	97.07	gold quality
ileal mucosa	UBERON:0000331	97.06	gold quality
peritoneum	UBERON:0002358	97.06	gold quality
omental fat pad	UBERON:0010414	97.06	gold quality
body of uterus	UBERON:0009853	97.02	gold quality
mucosa of stomach	UBERON:0001199	97.00	gold quality
putamen	UBERON:0001874	96.98	gold quality
epithelium of esophagus	UBERON:0001976	96.97	gold quality
caudate nucleus	UBERON:0001873	96.95	gold quality
endocervix	UBERON:0000458	96.92	gold quality
frontal cortex	UBERON:0001870	96.92	gold quality
ectocervix	UBERON:0012249	96.91	gold quality
adenohypophysis	UBERON:0002196	96.88	gold quality
colonic mucosa	UBERON:0000317	96.86	gold quality
adipose tissue of abdominal region	UBERON:0007808	96.86	gold quality
body of pancreas	UBERON:0001150	96.85	gold quality
ovary	UBERON:0000992	96.84	gold quality
right lung	UBERON:0002167	96.84	gold quality
jejunal mucosa	UBERON:0000399	96.81	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.80	gold quality
upper lobe of left lung	UBERON:0008952	96.80	gold quality
neocortex	UBERON:0001950	96.77	gold quality
minor salivary gland	UBERON:0001830	96.75	gold quality
spinal cord	UBERON:0002240	96.75	gold quality
adrenal tissue	UBERON:0018303	96.75	gold quality
substantia nigra	UBERON:0002038	96.74	gold quality
zone of skin	UBERON:0000014	96.71	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6379	no	808.30
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Tongue	tissue	591.6
Skeletal muscle	tissue	435.2	not detected
Heart muscle	tissue	256.1	high
Frontal cortex	tissue	256.0
Caudate putamen	tissue	245.9
Liver	tissue	165.9	medium
Parathyroid gland	tissue	147.0	not detected
Superior colliculi	tissue	144.4
Thalamus	tissue	140.1
Pons	tissue	133.1
Cerebral cortex	tissue	131.9	high
Somatosensory cortex	tissue	131.9
Spinal cord	tissue	128.7
Kidney	tissue	127.9	high
Midbrain	tissue	127.7
Medulla oblongata	tissue	127.4
Choroid plexus	tissue	126.4
Occipital cortex	tissue	116.1
Putamen	tissue	105.7
Substantia nigra	tissue	104.3
Motor cortex	tissue	103.1
Corpus callosum	tissue	102.6
Hippocampal formation	tissue	100.5
Duodenum	tissue	96.3	high
Rectum	tissue	95.6	high
Retrosplenial and cingulate cortex	tissue	92.7
Periaqueductal gray	tissue	90.7
Colon	tissue	90.4	high
Prefrontal cortex	tissue	90.3
Temporal cortex	tissue	89.8
Ventral forebrain	tissue	87.9
Retrosplenial cortex	tissue	87.9
Entorhinal cortex	tissue	87.5
Hypothalamus	tissue	85.2
Septum	tissue	84.2
Cerebellum	tissue	80.6	high
Adrenal gland	tissue	79.8	medium
Basal ganglia	tissue	77.3	medium
Small intestine	tissue	76.7	high
Insular cortex	tissue	72.8
Stomach 1	tissue	67.9	high
Amygdala	tissue	65.3
Olfactory bulb	tissue	65.1
Postcentral gyrus	tissue	62.1
Esophagus	tissue	58.2	medium
Adipose tissue	tissue	56.4	not detected
Tonsil	tissue	56.2	high
Smooth muscle	tissue	54.7	not detected
Ovary	tissue	54.5	not detected
Urinary bladder	tissue	53.8	medium
Locus coeruleus	tissue	51.7
Salivary gland	tissue	50.4	medium
Fallopian tube	tissue	49.4	medium
Breast	tissue	46.5	not detected
Nucleus accumbens	tissue	46.4
Vagina	tissue	46.3	low
Seminal vesicle	tissue	46.2	medium
Thymus	tissue	45.0
Pancreas	tissue	44.9	medium
Skin 1	tissue	44.7	high

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Ventral spinal cord (128.7), Dorsal spinal cord (107.4), White matter (102.6), Dorsal hippocampus (100.5), Ventral hippocampus (90.8).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting NDUFS2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

7 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-2277-3P	91.94	62.27	299

Functional genomics

gnomAD constraint: pLI 1.26e-05, LOEUF 0.69, missense Z 2.26 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000676972 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
1:161,202,386–161,202,479	57 / 42.3	1.35	no
1:161,202,480–161,212,474	339 / 433.8	0.78	no
1:161,212,475–161,214,190	72 / 118.9	0.61	no
DepMap (CRISPR cell-line fitness): dependent in 40.6% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): UACC-893 (-1.317), TE-11 (-1.284), KU812 (-1.283), MFE-296 (-1.243), KPL-1 (-1.241), EOL-1 (-1.22), SNU-1196 (-1.208), OCI-AML3 (-1.199), NCI-H2004 RT (-1.155), FU97 (-1.154), GSS (-1.153), LP-1 (-1.117), HEC-50B (-1.117), CAL-51 (-1.117), MEL-HO (-1.096).

Literature-anchored findings (GeneRIF, showing 40)

• Trx, dCBP, and Sbf1 are closely linked, physically and functionally, in the maintenance of Hox gene expression. (PMID:11701926)
• The Drosophila trithorax protein is a coactivator required to prevent re-establishment of polycomb silencing. (PMID:11973279)
• Genomic imprinting in Drosophila is maintained by the products of Suppressor of variegation and trithorax group, but not Polycomb group, genes. (PMID:12242505)
• Trithorax interacts with type 1 serine/threonine protein phosphatase. (PMID:12524522)
• This suggests that TRITHORAX bound to certain regulatory chromosome regions interacts with the adjacent elements of the nuclear scaffold, i.e., links the regions of actively transcribed genes with the nuclear matrix. (PMID:12669422)
• identified several members of the Polycomb and trithorax classes of genes required for the normal pattern of photoreceptor differentiation (PMID:15020417)
• Results suggest that protein phosphatase 1beta9C and Trithorax cooperate in Drosophila wing development. (PMID:15366010)
• Deletion analysis showed that the C-terminus of dDYRK2 modulated the interaction with SNR1 and TRX. (PMID:16671894)
• it is proposed that that the Trithorax complex, TAC1, promotes the mosaic pattern of Ubx expression by facilitating transcriptional elongation of bxd noncoding RNAs, which represses Ubx transcription (PMID:17174895)
• Data demonstrate that the Drosophila homologs of mixed-lineage leukemia protein and host cell factor 1, called Trithorax and dHCF, are both cleaved by Drosophila taspase 1. (PMID:17698583)
• Computational analysis ofmicroarray data, identified 25 clusters of genes potentially regulated by TRX; most of these clusters consist of genes that encode structural proteins involved in cuticle formation. (PMID:18783608)
• results indicate that DNA binding proteins serve as platforms to assist PcG and trxG binding. Furthermore, several DNA sequence features discriminate between PcG- and TRX-N-bound regions (PMID:19143474)
• Hsp90 cooperates with Trx at chromatin for maintaining the active expression state of targets like the Hox genes. (PMID:19144915)
• These findings establish a role for PRC2 and TRX in the modulation of organismal longevity and stress resistance and indicate that moderate perturbation of Polycomb silencing can increase longevity. (PMID:20018689)
• Polycomb and trithorax control genome expression by determining the alternative epigenetic states of chromatin for key developmental regulators (PMID:21254568)
• dHCF possesses Enhancer of TrxG and PcG (ETP) properties. (PMID:22174740)
• Data imply that Trx, Pc, and E(z) remain bound or rapidly rebind to nascent DNA in the absence of trimethylated histones during DNA replication in Drosophila embryos. (PMID:22921915)
• mutations in PcG components and in TrxG members found in chromatin remodeling complexes enhance the gcm dominant phenotype, suggesting a balanced action of these chromatin modifiers regulate Gcm function (PMID:23300465)
• CpG island encompassing the promoter and first exon of human DNMT3L gene is a PcG/TrX response element (PMID:24743422)
• From the Drosophila melanogaster vestigial (vg) Polycomb response element/Trithorax response element switches the status of the element. (PMID:25108384)
• Trithorax maintains the functional heterogeneity of neural stem cells through the transcription factor buttonhead. (PMID:25285447)
• Trithorax has a role in regulating systemic signaling during Drosophila imaginal disc regeneration (PMID:26487779)
• If ASH1 or TRX function is lost or reduced, heterochromatin can spread into these domains creating a sink that diverts heterochromatic proteins from other variegating locations, which then may express a suppressed phenotype. (PMID:27373142)
• Trithorax positively regulates gene expression in Drosophila and co-occupies PREs to antagonize Polycomb-dependent silencing. Trx-dependent H3K4 dimethylation (H3K4me2) marks Drosophila PREs and maintains the developmental expression pattern of nearby genes. (PMID:27447986)
• Taken together, these data indicate that Atrophin is a major Trithorax-like cofactor that functions to moderate developmental gene transcription. (PMID:28327288)
• Mrg15 is a subunit of the Ash1 complex, a stimulator of Ash1 enzymatic activity and a critical regulator of the TrxG protein function of Ash1 in Drosophila. (PMID:29158494)
• Control of the gene activity by polycomb and trithorax group proteins in Drosophila (PMID:29372960)
• we demonstrate that the evolutionary conserved Lim3 core promoter provides basic Lim3 expression, whereas structural changes in the Lim3 PRE of distal promoter provide stage-, and tissue-specific Lim3 expression. Therefore, we hypothesize that PcG/TrxG proteins, which are directly involved in Lim3 transcription regulation, participate in lifespan control. (PMID:29555581)
• Trx and Grx have both, common and specific protein Cys redox targets and that down regulation of either redoxin has markedly different metabolic outcomes. They reflect the delicate sensitivity of redox equilibrium to changes in any of the elements involved and the difficulty of forecasting metabolic responses to redox environmental changes. (PMID:30639960)
• Trx, Ash1, and CBP proteins are required for the correct chromosome segregation and that Ash1 and CBP mediate for Cid/CENP-A recruitment at centromeres through post-translational histone modifications. (PMID:31203392)
• Dynamic Competition of Polycomb and Trithorax in Transcriptional Programming. (PMID:31928411)
• Distinct Roles for COMPASS Core Subunits Set1, Trx, and Trr in the Epigenetic Regulation of Drosophila Heart Development. (PMID:38139143)
• Our results confirm that NDUFS2 is a mutational hotspot in Caucasian children with isolated complex I deficiency and recommend the routine diagnostic investigation of this gene in patients with Leigh or Leigh-like phenotypes. (PMID:20819849)
• The NDUFS2 mutation affects complex I enzymatic function. (PMID:22036843)
• study describes clinical, radiological, biochemical and molecular data of 6 patients with Leigh syndrome with novel mutations in NDUFV1 and NDUFS2; 2 siblings were compound heterozygotes for an undescribed E104A mutation in NDUFS2 (PMID:23266820)
• NDUFAF7 methylates arginine 85 in the NDUFS2 subunit of human complex I. (PMID:24089531)
• Results found nominal significant associations of 2 SNPs in the NDUFS1 gene and 4 SNPs in the NDUFS2 gene with early onset schizophrenia (EOS), but none of these associations survived the Bonferroni correction. (PMID:26053550)
• compound heterozygosity for severe and hypomorphic NDUFS2 mutations can cause non-syndromic hereditary optic neuropathy. (PMID:28031252)
• findings uncover a novel S100A4 function and highlight its importance in controlling NDUFS2 expression to regulate the plasticity of mitochondrial metabolism and thereby promote the invasive and metastatic capacity in lung cancer (PMID:30885944)
• Complex I protein NDUFS2 is vital for growth, ROS generation, membrane integrity, apoptosis, and mitochondrial energetics. (PMID:33744462)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufs2	ENSDARG00000007526
mus_musculus	Ndufs2	ENSMUSG00000013593
rattus_norvegicus	Ndufs2	ENSRNOG00000038372
drosophila_melanogaster	ND-49	FBGN0039909
caenorhabditis_elegans		WBGENE00001520
caenorhabditis_elegans		WBGENE00006463

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2385112) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 4 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal embryo size	1
preweaning lethality, complete penetrance	1
embryonic lethality prior to organogenesis	1
embryonic lethality prior to tooth bud stage	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Mycobacterium avium 104	A0QJV0	100.0%	Diamond
Mycobacterium tuberculosis variant bovis BCG str. Pasteur 1173P2	A1KNE4	100.0%	Diamond
Cereibacter sphaeroides ATCC 17029	A3PIX1	100.0%	Diamond
Mycobacterium tuberculosis H37Ra	A5U7G4	100.0%	Diamond
Rickettsia bellii OSU 85-389	A8GX80	100.0%	Diamond
Leptospira biflexa serovar Patoc strain ‘Patoc 1 (Ames)’	B0SFT7	100.0%	Diamond
Leptospira biflexa serovar Patoc strain ‘Patoc 1 (Paris)’	B0SP85	100.0%	Diamond
Mycobacterium tuberculosis variant bovis AF2122/97	P65570	100.0%	Diamond
Mycobacterium tuberculosis CDC1551	P9WJH4	100.0%	Diamond
Mycobacterium tuberculosis H37Rv	P9WJH5	100.0%	Diamond
Rickettsia bellii RML369-C	Q1RJI9	100.0%	Diamond
Cereibacter sphaeroides 2.4.1	Q3J3F8	100.0%	Diamond
Mycobacterium avium subsp. paratuberculosis K-10	Q73V12	100.0%	Diamond
Pan troglodytes	Q0MQG5	99.8%	Diamond
Dictyostelium discoideum	Q23883	99.8%	Diamond
Dictyostelium citrinum	Q2LCR5	99.8%	Diamond
Rickettsia rickettsii str. ‘Sheila Smith’	A8GRR5	99.7%	Diamond
Rickettsia rickettsii str. Iowa	B0BX71	99.7%	Diamond
Gorilla gorilla gorilla	Q0MQG4	99.6%	Diamond
Mycobacterium ulcerans Agy99	A0PR41	99.5%	Diamond
Mycobacterium marinum M	B2HGE5	99.5%	Diamond
Thermus thermophilus HB8	Q56220	99.5%	Diamond
Ehrlichia ruminantium str. Gardel	Q5FGV3	99.5%	Diamond
Ehrlichia ruminantium str. Welgevonden	Q5HB88	99.5%	Diamond
Thermus thermophilus HB27	Q72GD1	99.5%	Diamond
Rhizobium etli CIAT 652	B3PY59	99.3%	Diamond
Rhizobium etli CFN 42	Q2K3U2	99.3%	Diamond
Rickettsia massiliae MTU5	A8F1C5	99.2%	Diamond
Rickettsia conorii str. Malish 7	Q92ID8	99.2%	Diamond
Pongo pygmaeus	Q0MQG3	99.1%	Diamond
Orientia tsutsugamushi str. Boryong	A5CES2	99.0%	Diamond
Orientia tsutsugamushi str. Ikeda	B3CSH1	99.0%	Diamond
Sinorhizobium medicae WSM419	A6UFK4	98.8%	Diamond
Sinorhizobium meliloti 1021	P56908	98.8%	Diamond
Anaeromyxobacter dehalogenans 2CP-C	Q2IL06	98.6%	Diamond
Bradyrhizobium sp. BTAi1	A5EK97	98.2%	Diamond
Rickettsia felis Marseille-URRWFXCal2	Q4UM08	98.2%	Diamond
Rickettsia typhi str. Wilmington	Q68X19	98.2%	Diamond
Rickettsia prowazekii str. Madrid E	Q9ZDH4	98.2%	Diamond
Cereibacter sphaeroides ATCC 17025	A4WU31	97.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
USP21	protein-coding	27005
UFC1	protein-coding	51506
PPOX	protein-coding	5498
B4GALT3	protein-coding	8703
ADAMTS4	protein-coding	9507
FCER1G	protein-coding	2207
APOA2	protein-coding	336
MIR5187	ncRNA	100847090
TOMM40L	protein-coding	84134
NR1I3	protein-coding	9970

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial — O75306 (reviewed: O75306)

Alternative names: Complex I-49kD, NADH-ubiquinone oxidoreductase 49 kDa subunit

All UniProt accessions (18): A0A7I2V2B9, A0A7I2V2P1, A0A7I2V3J6, A0A7I2V410, A0A7I2V4G5, A0A7I2V4W5, A0A7I2V4X8, A0A7I2V517, A0A7I2V596, O75306, A0A7I2V5D5, A0A7I2V5E2, A0A7I2V5G4, A0A7I2V5X7, A0A7I2V630, A0A7I2YQD8, A0A7I2YQG7, A0A7I2YQX7

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 of complex I. Essential for the assembly of complex I. Redox-sensitive, critical component of the oxygen-sensing pathway in the pulmonary vasculature which plays a key role in acute pulmonary oxygen-sensing and hypoxic pulmonary vasoconstriction. Plays an important role in carotid body sensing of hypoxia. Essential for glia-like neural stem and progenitor cell proliferation, differentiation and subsequent oligodendrocyte or neuronal maturation.

Subunit / interactions. Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits. Component of the iron-sulfur (IP) fragment of the enzyme. Interacts with NDUFAF3. Interacts with NDUFAF7. Interacts with CERS2.

Subcellular location. Mitochondrion inner membrane.

Post-translational modifications. Dimethylation at Arg-118 by NDUFAF7 takes place after NDUFS2 assembles into the complex I, leading to stabilize the early intermediate complex.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 6 (MC1DN6) [MIM:618228] 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. MC1DN6 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry. Leber-like hereditary optic neuropathy, autosomal recessive 2 (LHONAR2) [MIM:620569] An autosomal recessive form of Leber hereditary optic neuropathy, a mitochondrial disease resulting in bilateral painless loss of central vision due to selective degeneration of the retinal ganglion cells and their axons. LHONAR2 is characterized by subacute bilateral or asymmetrical visual loss, optic nerve pseudoedema and peripapillary telangiectasia in the early phase of the disease, and eventual partial recovery in some patients. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 [4Fe-4S] cluster.

Similarity. Belongs to the complex I 49 kDa subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
O75306-1	1	yes
O75306-2	2

RefSeq proteins (8): NP_001159631, NP_001364227, NP_001364228, NP_001364229, NP_001364230, NP_001364231, NP_001397818, NP_004541 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001135	NADH_Q_OxRdtase_suD	Domain
IPR014029	NADH_UbQ_OxRdtase_49kDa_CS	Conserved_site
IPR022885	NDH1_su_D/H	Family
IPR029014	NiFe-Hase_large	Homologous_superfamily

Pfam: PF00346

Catalyzed reactions (Rhea)

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

UniProt features (56 total): helix 20, strand 12, sequence variant 10, turn 5, binding site 3, modified residue 2, transit peptide 1, chain 1, sequence conflict 1, splice variant 1

Structure

Experimental structures (PDB)

8 structures by resolution:

PDB	Title	Method	Resolution (Å)
9I4I	High resolution Cryo-EM structure of human complex I in mitochondria	ELECTRON MICROSCOPY	2.63
9TI4	High resolution Cryo-EM structure of human complex I in mitochondria	ELECTRON MICROSCOPY	2.66
5XTB	Cryo-EM structure of human respiratory complex I matrix arm	ELECTRON MICROSCOPY	3.4
9CWT	Human kidney respiratory complex I	ELECTRON MICROSCOPY	3.44
5XTC	Cryo-EM structure of human respiratory complex I transmembrane arm	ELECTRON MICROSCOPY	3.7
5XTD	Cryo-EM structure of human respiratory complex I	ELECTRON MICROSCOPY	3.7
5XTH	Cryo-EM structure of human respiratory supercomplex I1III2IV1	ELECTRON MICROSCOPY	3.9
5XTI	Cryo-EM architecture of human respiratory chain megacomplex-I2III2IV2	ELECTRON MICROSCOPY	17.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75306-F1	89.62	0.81

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Metabolic proteins, Predicted membrane proteins, Predicted intracellular proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital disorders of metabolism, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria; calyx; connecting piece

Antibody reliability (HPA): IH enhanced · IF approved

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 (3)

Position	Role
326	[4Fe-4S] cluster
332	[4Fe-4S] cluster
347	[4Fe-4S] cluster

Post-translational modifications (2)

Type	Positions
N6-acetyllysine	62
Symmetric dimethylarginine	118

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

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

MSigDB gene sets: 431 (showing top): MODULE_93, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, MODY_HIPPOCAMPUS_POSTNATAL, MODULE_77, LFA1_Q6, MORF_HDAC1, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_NEUROGENESIS, 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_NEURAL_PRECURSOR_CELL_PROLIFERATION

GO Biological Process (11): mitochondrial electron transport, NADH to ubiquinone (GO:0006120), aerobic respiration (GO:0009060), neurogenesis (GO:0022008), mitochondrial respiratory chain complex I assembly (GO:0032981), gliogenesis (GO:0042063), mitochondrial ATP synthesis coupled electron transport (GO:0042775), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), neural precursor cell proliferation (GO:0061351), cellular response to oxygen levels (GO:0071453), respiratory electron transport chain (GO:0022904), proton transmembrane transport (GO:1902600)

GO Molecular Function (13): NADH dehydrogenase (ubiquinone) activity (GO:0008137), electron transfer activity (GO:0009055), oxidoreductase activity, acting on NAD(P)H (GO:0016651), oxygen sensor activity (GO:0019826), ubiquitin protein ligase binding (GO:0031625), metal ion binding (GO:0046872), quinone binding (GO:0048038), NAD binding (GO:0051287), 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 (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), respiratory chain complex I (GO:0045271)

Reactome top-level categories

3 top-level categories:

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

GO top-level categories

44 GO namespaces:

Category	Terms
mitochondrion	3
cellular respiration	2
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
nervous system development	1
cell differentiation	1
NADH dehydrogenase complex assembly	1
mitochondrial respiratory chain complex assembly	1
neurogenesis	1
ATP synthesis coupled electron transport	1
oxidative phosphorylation	1
proton motive force-driven ATP synthesis	1
cell population proliferation	1
response to oxygen levels	1
cellular response to chemical stimulus	1
electron transport chain	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
molecular_function	1
oxidoreductase activity	1
oxygen binding	1
molecular sensor activity	1
ubiquitin-like protein ligase binding	1
cation binding	1
small molecule binding	1
adenyl nucleotide 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

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 9 of 28 annotations. The rest are phylogenetic / computational / electronic (IEA).

9 experimentally-supported GO terms:

GO term	NS	Evidence
cellular response to oxygen levels	BP	mutant phenotype
mitochondrial ATP synthesis coupled electron transport	BP	mutant phenotype
mitochondrial electron transport, NADH to ubiquinone	BP	mutant phenotype
mitochondrial inner membrane	CC	direct assay
mitochondrion	CC	direct assay
respiratory chain complex I	CC	direct assay
NADH dehydrogenase (ubiquinone) activity	MF	mutant phenotype
oxygen sensor activity	MF	mutant phenotype
ubiquitin protein ligase binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 2,917 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFS2	NDUFS3	O75489	963
NDUFS2	NDUFS1	P28331	956
NDUFS2	NDUFS6	O75380	944
NDUFS2	NDUFS7	O75251	942
NDUFS2	NDUFS8	O00217	939
NDUFS2	NDUFV1	P49821	935
NDUFS2	NDUFS4	O43181	933
NDUFS2	NDUFV2	P19404	930
NDUFS2	NDUFA5	Q16718	874
NDUFS2	NDUFS5	O43920	872
NDUFS2	NDUFAF5	Q5TEU4	820
NDUFS2	NDUFA2	O43678	805
NDUFS2	NDUFA11	Q86Y39	800
NDUFS2	MT-ND4	P03905	797
NDUFS2	NDUFAF4	Q9P032	793

IntAct

Human interaction partners of NDUFS2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

16 partners by confidence:

Partner	Interaction type	MIscore	Records
NDUFS3	association	0.850	5
NDUFA9	physical association	0.740	1
NDUFV2	association	0.730	1
NDUFAF3	physical association	0.560	2
DHRS4	association	0.530	2
OSMR	association	0.500	4
CENPU	physical association	0.370	1
EGR2	physical association	0.370	1
HMOX2	physical association	0.370	1
PCNA	physical association	0.370	1
TNFRSF14	physical association	0.370	1
GATD3	association	0.350	2
ACAD9	association	0.350	1
ECSIT	association	0.350	1
MCC	association	0.350	1
MKLN1	physical association	0.000	1

BioGRID (425 interactions; top human partners by supporting records): NDUFS3 (Affinity Capture-MS; 11 records), NDUFA7 (Affinity Capture-MS; 7 records), NDUFS1 (Co-fractionation; 5 records), NDUFS7 (Affinity Capture-MS; 5 records), NDUFV1 (Co-fractionation; 5 records), NDUFV2 (Co-fractionation; 5 records), NDUFA10 (Co-fractionation; 4 records), NDUFA9 (Affinity Capture-MS; 4 records), NDUFS6 (Affinity Capture-MS; 4 records), AMBRA1 (Affinity Capture-MS; 3 records), NDUFA13 (Affinity Capture-MS; 3 records), NDUFB11 (Affinity Capture-MS; 3 records), NDUFS5 (Affinity Capture-MS; 3 records), NDUFS8 (Co-fractionation; 3 records), PARK2 (Affinity Capture-MS; 3 records)

SIGNOR signaling

3 signaling interactions:

A	Effect	B	Mechanism
NDUFS2	“form complex”	“NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I”	binding
CDK1	“up-regulates activity”	NDUFS2	phosphorylation
CyclinB/CDK1	“up-regulates activity”	NDUFS2	phosphorylation

Protein complexes (CORUM) (8)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

8 complexes by size:

Complex	Subunits	Members
★ Respiratory chain complex I (holoenzyme), mitochondrial	44	NDUFS7, NDUFB3, NDUFB5, MT-ND1, NDUFA12, NDUFA5, NDUFA6, NDUFA7, NDUFV3, MT-ND2, MT-ND5, NDUFB2, MT-ND3, NDUFA11, NDUFA2, NDUFB9, NDUFS1, MT-ND6, NDUFA13, NDUFAB1, NDUFB4, NDUFS6, NDUFS8, NDUFA10, NDUFB10, NDUFB11, NDUFC2, NDUFS5, MT-ND4L, NDUFA3, NDUFA8, NDUFB1, NDUFB6, NDUFB8, NDUFS3, NDUFV2, NDUFA4, NDUFA9, NDUFB7, NDUFC1, NDUFS2, NDUFV1, NDUFA1, NDUFS4
★ Respiratory chain complex I (lambda subunit), mitochondrial	16	NDUFS2, NDUFS3, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFA11, NDUFA2, NDUFA5, NDUFA7, NDUFS4, NDUFV2, NDUFA12, NDUFV3, NDUFA13, NDUFS1
★ Respiratory chain complex I (intermediate), mitochondrial	11	NDUFA9, NDUFS3, NDUFS4, NDUFS5, NDUFB6, NDUFS2, NDUFS7, NDUFV2, MT-ND1, NDUFA2, NDUFA6
★ Respiratory chain complex I (incomplete intermediate), mitochondrial	11	NDUFS4, NDUFS7, NDUFV1, NDUFV2, NDUFV3, NDUFA10, NDUFA9, NDUFS2, NDUFS6, NDUFB8, NDUFS1
★ Respiratory chain complex I (intermediate VII/650kD), mitochondrial	10	NDUFA2, NDUFA9, NDUFS7, NDUFV2, NDUFA6, NDUFS2, NDUFS3, NDUFS4, NDUFS5, MT-ND1
★ Respiratory chain complex I (intermediate V/380kD and VI/480kD), mitochondrial	5	NDUFS2, NDUFS3, MT-ND1, NDUFA2, NDUFA9
★ Respiratory chain complex I (intermediate IV/310kD), mitochondrial	4	MT-ND1, NDUFA9, NDUFS2, NDUFS3
★ Respiratory chain complex I (intermediate I/200kD and III/250kD), mitochondrial	3	NDUFA9, NDUFS2, NDUFS3

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 16 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	6	70.9×	8e-09
Aerobic respiration and respiratory electron transport	6	37.9×	2e-07
Respiratory electron transport	5	34.0×	5e-06

Disease & clinical

Genetic variants

Variant evidence for NDUFS2: 266 ClinVar records (11 pathogenic / likely pathogenic); 8 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	5
Uncertain significance	114
Likely benign	78
Benign	15

Top pathogenic / likely-pathogenic (11)

Showing all 11 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
4312718	NM_001377299.1(NDUFS2):c.1102C>T (p.Arg368Ter)	Pathogenic	criteria provided, single submitter	3
872511	NM_001377299.1(NDUFS2):c.442G>A (p.Glu148Lys)	Pathogenic	criteria provided, single submitter	1
1451468	NM_001377299.1(NDUFS2):c.128G>A (p.Trp43Ter)	Pathogenic	criteria provided, single submitter	1
4714351	NM_001377299.1(NDUFS2):c.90del (p.Ser31fs)	Pathogenic	criteria provided, single submitter	1
4312697	NM_001377299.1(NDUFS2):c.805C>T (p.Arg269Ter)	Likely pathogenic	criteria provided, single submitter	2
522715	NM_001377299.1(NDUFS2):c.268G>A (p.Ala90Thr)	Likely pathogenic	criteria provided, single submitter	1
1324786	NM_001377299.1(NDUFS2):c.646C>T (p.Arg216Ter)	Likely pathogenic	criteria provided, single submitter	1
1478205	NM_001377299.1(NDUFS2):c.1212+1G>T	Likely pathogenic	criteria provided, single submitter	1
2010294	NM_001377299.1(NDUFS2):c.867-1G>A	Likely pathogenic	criteria provided, single submitter	1
6710	NM_001377299.1(NDUFS2):c.686C>A (p.Pro229Gln)	Pathogenic	no assertion criteria provided	1
2627943	NM_001377299.1(NDUFS2):c.923A>G (p.Tyr308Cys)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore NDUFS2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 29 predictions of 717):

Position(s)	Effect	Δscore	Sites
1:161206399	acceptor_gain	1.0000
1:161209191–161209192	acceptor_loss	1.0000	5
1:161209314–161209315	donor_loss	1.0000	3
1:161209481–161209482	acceptor_loss	1.0000	4
1:161209596–161209597	donor_loss	1.0000	5
1:161210589–161210590	acceptor_loss	1.0000	3
1:161210711–161210712	donor_loss	1.0000	5
1:161212334	acceptor_gain	1.0000
1:161212341	acceptor_gain	1.0000
1:161212347	acceptor_gain	1.0000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	3.63e-08
Glioblastoma Multiforme (validation)	favorable	5.35e-05

Disease associations

OMIM: gene MIM:602985 | disease phenotypes: MIM:620569, MIM:535000, MIM:618228

GenCC curated gene-disease

3 curated gene-disease records:

Disease	Classification	Inheritance	Records
mitochondrial complex I deficiency, nuclear type 6	Definitive	Autosomal recessive	5
Leber hereditary optic neuropathy	Supportive	Mitochondrial
mitochondrial complex I deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity

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

2 validity classifications:

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR
Leigh syndrome	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (14 panels, 10 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

14 panels:

Panel	Rating
Hypotonic infant	green
Inherited white matter disorders	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Mitochondrial disorder with complex I deficiency	green
Mitochondrial disorders	green
Paediatric or syndromic cardiomyopathy	green
Possible mitochondrial disorder, nuclear genes	green
Undiagnosed metabolic disorders	green
White matter disorders and cerebral calcification - childhood onset	green
Early onset or syndromic epilepsy	amber
Optic neuropathy	amber
Paediatric disorders	amber
Unexplained death in infancy and sudden unexplained death in childhood	amber

Mondo (4): Leber-like hereditary optic neuropathy, autosomal recessive 2 (MONDO:0958197), Leber hereditary optic neuropathy (MONDO:0010788), mitochondrial complex I deficiency, nuclear type 6 (MONDO:0032611), mitochondrial complex I deficiency (MONDO:0100133)

Orphanet (1): Leber hereditary optic neuropathy (Orphanet:104)

HPO phenotypes

showing 60 of 78 phenotypes (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:0000512	Abnormal electroretinogram
HP:0000529	Progressive visual loss
HP:0000543	Optic disc pallor
HP:0000551	Color vision defect
HP:0000576	Centrocecal scotoma
HP:0000603	Central scotoma
HP:0000618	Blindness
HP:0000622	Blurred vision
HP:0000639	Nystagmus
HP:0000642	Red-green dyschromatopsia
HP:0000648	Optic atrophy
HP:0000649	Abnormality of visual evoked potentials
HP:0000666	Horizontal nystagmus
HP:0000817	Reduced eye contact
HP:0000819	Diabetes mellitus
HP:0001138	Optic neuropathy
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001639	Hypertrophic cardiomyopathy
HP:0001712	Left ventricular hypertrophy
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0002013	Vomiting
HP:0002093	Respiratory insufficiency
HP:0002104	Apnea
HP:0002119	Ventriculomegaly
HP:0002151	Increased circulating lactate concentration
HP:0002174	Postural tremor
HP:0002240	Hepatomegaly
HP:0002352	Leukoencephalopathy
HP:0002376	Developmental regression
HP:0002415	Leukodystrophy
HP:0002421	Poor head control
HP:0002490	Increased CSF lactate
HP:0003128	Lactic acidosis
HP:0003198	Myopathy
HP:0003202	Skeletal muscle atrophy
HP:0003542	Increased circulating pyruvate concentration
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003623	Neonatal onset
HP:0003737	Mitochondrial myopathy
HP:0004309	Ventricular preexcitation
HP:0004900	Severe lactic acidosis
HP:0007256	Abnormal pyramidal sign

GWAS associations

8 associations:

Study	Trait	p-value
GCST007800_18	Asthma (childhood onset)	3e-32
GCST007798_20	Asthma	9e-12
GCST005038_71	Allergic disease (asthma, hay fever or eczema)	1e-11
GCST004608_41	Granulocyte percentage of myeloid white cells	2e-10
GCST009719_21	Allergic rhinitis	4e-10
GCST009720_35	Asthma	1e-9
GCST008916_64	Asthma	2e-8
GCST007797_50	Asthma onset (childhood vs adult)	1e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0004847	age at onset

MeSH disease descriptors

2 disease descriptors:

Descriptor	Name	Tree numbers
D029242	Optic Atrophy, Hereditary, Leber	C10.292.700.225.500.400; C10.574.500.662.400; C11.270.564.400; C11.640.451.451.400; C16.320.290.564.400; C16.320.400.630.400; C18.452.660.670
C537475	Mitochondrial complex I deficiency *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363065 (PROTEIN COMPLEX), CHEMBL3039 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 2 human assays (3 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

16 potent at pChembl≥5 of 26 total, top 14 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.48	IC50	33	nM	CHEMBL4798829
7.34	Kd	45.26	nM	CHEMBL3752910
7.34	ED50	45.26	nM	CHEMBL3752910
7.10	IC50	79	nM	CHEMBL4798829
6.06	IC50	870	nM	R-(+)-MARMIN-6’-UNDECANOATE
6.04	IC50	920	nM	R-(+)-MARMIN-6’-LINOLEATE
5.91	Kd	1236	nM	CHEMBL5653589
5.91	ED50	1236	nM	CHEMBL5653589
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

10 with measured affinity, of 32 total; 6 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148853: Binding affinity to human NDUFS2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0453	uM
[(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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148853: Binding affinity to human NDUFS2 incubated for 45 mins by Kinobead based pull down assay	kd	1.2362	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

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	affects cotreatment, decreases expression	3
bisphenol A	increases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Arsenic	decreases expression, increases abundance, increases methylation, affects cotreatment	2
Valproic Acid	increases methylation, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
beta-lapachone	increases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Aerosols	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cocaine	affects expression	1
Doxorubicin	increases expression	1
Isoniazid	decreases expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1

ChEMBL screening assays

11 unique, capped per target: 10 binding, 1 functional

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*
CHEMBL5210044	Functional	Affinity Phenotypic Cellular interaction (Proliferation assay (CellTiter-Glo ATP assay in human lung H1299 cells)) EUB0000752a NDUFS2	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomics Library wave 3

Cellosaurus cell lines

8 cell lines: 5 cancer cell line, 2 transformed cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0D2	HEK293 NDUSF2 KO	Transformed cell line	Female
CVCL_D1P5	Abcam K-562 NDUFS2 KO	Cancer cell line	Female
CVCL_D2KQ	Abcam Raji NDUFS2 KO	Cancer cell line	Male
CVCL_D9L4	Ubigene HEK293 NDUFS2 KO	Transformed cell line	Female
CVCL_EQ48	8807	Finite cell line	Female
CVCL_TA18	HAP1 NDUFS2 (-) 1	Cancer cell line	Male
CVCL_TA19	HAP1 NDUFS2 (-) 2	Cancer cell line	Male
CVCL_WQ07	Abcam Jurkat NDUFS2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

31 trials:

NCT	Phase	Status	Title
NCT03293524	Phase 3	COMPLETED	Efficacy & Safety Study of Bilateral IVT Injection of GS010 in LHON Subjects Due to the ND4 Mutation for up to 1 Year
NCT03406104	Phase 3	COMPLETED	RESCUE and REVERSE Long-term Follow-up
NCT07406854	Phase 3	ACTIVE_NOT_RECRUITING	A Phase 3, Multicenter, Randomized, Double-Masked, Sham-Controlled Clinical Trial for Leber’s Hereditary Optic Neuropathy (LHON) Associated With ND4 Mutation
NCT05162768	Phase 3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT02176733	Phase 2	UNKNOWN	Trial of Cyclosporine in the Acute Phase of Leber Hereditary Optic Neuropathy
NCT02544217	Phase 1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT07258667	Phase 1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT01064505	Phase 1	COMPLETED	Safety Study of a Single IVT Injection of QPI-1007 in Chronic Optic Nerve Atrophy and Recent Onset NAION Patients
NCT05147701	Phase 1	RECRUITING	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for NAION
NCT03153293	Phase 2/3	UNKNOWN	A Single Intravitreal Injection of rAAV2-ND4 for the Treatment of Leber’s Hereditary Optic Neuropathy
NCT02064569	Phase 1/2	COMPLETED	Safety Evaluation of Gene Therapy in Leber Hereditary Optic Neuropathy (LHON) Patients
NCT05293626	Phase 1/2	ACTIVE_NOT_RECRUITING	Gene Therapy Clinical Trial for the Treatment of Leber’s Hereditary Optic Neuropathy Associated With ND4 Mutations
NCT05820152	Phase 1/2	TERMINATED	Gene Therapy Clinical Trial for the Treatment of Leber’s Hereditary Optic Neuropathy Associated With ND1 Mutations
NCT01267422	Not specified	COMPLETED	Safety and Efficacy Study of rAAV2-ND4 Treatment of Leber Hereditary Optic Neuropathy (LHON)
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT01892943	Not specified	COMPLETED	Leber Hereditary Optic Neuropathy (LHON) Historical Case Record Survey
NCT03011541	Not specified	RECRUITING	Stem Cell Ophthalmology Treatment Study II
NCT03295071	Not specified	COMPLETED	REALITY LHON Registry
NCT03428178	Not specified	UNKNOWN	Efficacy Study of Gene Therapy for The Treatment of Acute LHON Onset Within Three Months
NCT03475173	Not specified	RECRUITING	New Non-invasive Modalities for Assessing Retinal Structure and Function
NCT03672968	Not specified	NO_LONGER_AVAILABLE	EAP_GS010_single Patient
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06376279	Not specified	ENROLLING_BY_INVITATION	Genetic Diagnosis in Inborn Errors of Metabolism
NCT06682819	Not specified	RECRUITING	Metabolomics Analysis According to the Retinal Nerve Fiber Layer in Patients With NOHL Mutations (MétabOCT)
NCT02882477	Phase 2/3	UNKNOWN	Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone and Incretin Based Therapy
NCT01834079	Phase 1/2	UNKNOWN	Study the Safety and Efficacy of Bone Marrow Derived Autologous Cells for the Treatment of Optic Nerve Disease
NCT04680143	Phase 1/2	COMPLETED	Systemic Erythropoietin Injection in Patients Having Optic Atrophy
NCT04580979	Not specified	COMPLETED	Natural History Study of FDXR Mutation-related Mitochondriopathy
NCT04594590	Not specified	COMPLETED	Natural History Study of SLC25A46 Mutation-related Mitochondriopathy
NCT04723160	Not specified	COMPLETED	Computer Aided Diagnosis of Multiple Eye Fundus Diseases From Color Fundus Photograph
NCT06390579	Not specified	COMPLETED	Building Research With Artificial Intelligence in Neuro-Ophthalmology

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for NDUFS2 across ~30M SureChEMBL compounds — explore on Sugi Predict.