NDUFA13

Summary

NDUFA13 (NADH:ubiquinone oxidoreductase subunit A13, HGNC:17194) is a protein-coding gene on chromosome 19p13.11, encoding NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 (Q9P0J0). 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: 23.8% of cell lines).

This gene encodes a subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), which functions in the transfer of electrons from NADH to the respiratory chain. The protein is required for complex I assembly and electron transfer activity. The protein binds the signal transducers and activators of transcription 3 (STAT3) transcription factor, and can function as a tumor suppressor. The human protein purified from mitochondria migrates at approximately 16 kDa. Transcripts originating from an upstream promoter and capable of expressing a protein with a longer N-terminus have been found, but their biological validity has not been determined.

Source: NCBI Gene 51079 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial complex I deficiency, nuclear type 28 (Strong, GenCC) — +4 more curated relationships
• GWAS associations: 13
• Clinical variants (ClinVar): 52 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 26
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 23.8% of screened cell lines
• MANE Select transcript: NM_015965

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17194
Approved symbol	NDUFA13
Name	NADH:ubiquinone oxidoreductase subunit A13
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	CGI-39, CDA016, GRIM-19, GRIM19, B16.6
Ensembl gene	ENSG00000186010
Ensembl biotype	protein_coding
OMIM	609435
Entrez	51079

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 11 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000428459, ENST00000502506, ENST00000503283, ENST00000507754, ENST00000511180, ENST00000511584, ENST00000606722, ENST00000880579, ENST00000911742, ENST00000911743, ENST00000911744, ENST00000911745, ENST00000911746, ENST00000941958, ENST00000941959

RefSeq mRNA: 1 — MANE Select: NM_015965 NM_015965

CCDS: CCDS12404

Canonical transcript exons

ENST00000507754 — 5 exons

Exon	Start	End
ENSE00002067953	19528007	19528198
ENSE00002772751	19516225	19516332
ENSE00003702529	19527281	19527352
ENSE00003704912	19526182	19526260
ENSE00003707311	19527701	19527770

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 129.8348 / max 663.6615, expressed in 1827 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174801	129.4224	1827
174800	0.3614	123
174799	0.0510	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.86	gold quality
heart left ventricle	UBERON:0002084	99.72	gold quality
right atrium auricular region	UBERON:0006631	99.64	gold quality
right testis	UBERON:0004534	99.62	gold quality
putamen	UBERON:0001874	99.61	gold quality
left testis	UBERON:0004533	99.58	gold quality
prefrontal cortex	UBERON:0000451	99.57	gold quality
caudate nucleus	UBERON:0001873	99.57	gold quality
nucleus accumbens	UBERON:0001882	99.57	gold quality
substantia nigra	UBERON:0002038	99.56	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.56	gold quality
frontal cortex	UBERON:0001870	99.55	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.54	gold quality
temporal lobe	UBERON:0001871	99.53	gold quality
hypothalamus	UBERON:0001898	99.53	gold quality
anterior cingulate cortex	UBERON:0009835	99.53	gold quality
pituitary gland	UBERON:0000007	99.52	gold quality
amygdala	UBERON:0001876	99.52	gold quality
cerebral cortex	UBERON:0000956	99.51	gold quality
adenohypophysis	UBERON:0002196	99.51	gold quality
right frontal lobe	UBERON:0002810	99.51	gold quality
heart	UBERON:0000948	99.49	gold quality
Ammon’s horn	UBERON:0001954	99.49	gold quality
primary visual cortex	UBERON:0002436	99.49	gold quality
adult mammalian kidney	UBERON:0000082	99.47	gold quality
brain	UBERON:0000955	99.46	gold quality
mucosa of transverse colon	UBERON:0004991	99.46	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.45	gold quality
superior frontal gyrus	UBERON:0002661	99.42	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.42	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	826.63
E-ANND-3	yes	18.79
E-HCAD-10	yes	12.87
E-MTAB-8142	yes	10.33
E-MTAB-8410	yes	3.66
E-HCAD-31	no	18.62

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT3

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 23.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• results collectively indicate that viral interferon regulatory factor 1 modulates interferon/retinoic acid-cell death signals via interactions with GRIM19 (PMID:12163600)
• GRIM-19 is an inhibitor of signal transducer and activator of transcription 3 (PMID:12867595)
• GRIM-19 may be a key component in NOD2-mediated innate mucosal responses and serve to regulate intestinal epithelial cell responses to microbes (PMID:15753091)
• The IFN-beta- and tretinoin-induced GRIM-19 is upregulated during focal cerebral ischemia. (PMID:17523870)
• GRIM-19 suppresses constitutive STAT3-induced cellular transformation in vitro and in vivo by down-regulating the expression of a number of cellular genes involved in cell proliferation and apoptosis (PMID:17616678)
• The low expression or absence of GRIM-19 may play an important role in the tumorigenesis of colorectal carcinoma. (PMID:17626740)
• GRIM-19 not only blocks src-induced gene expression through STAT3 but also the activation of cell adhesion molecules. (PMID:17823279)
• results indicate that the high affinity between U95 early viral protein and GRIM-19 may be closely linked to the detrimental effect of HHV-6B infection on mitochondria. (PMID:17928352)
• GRIM-19 genetic alternations do not seem play a major role in predisposition to CD (PMID:18022871)
• GRIM19 in colon cancer cell lines could promote apoptotic cell death (PMID:18278448)
• GRIM-19 is required for electron transfer activity of complex I, and disruption of mitochondrial transmembrane potential by GRIM-19 mutants enhances the cells’ sensitivity to apoptotic stimuli. (PMID:18287540)
• GRIM-19 expression is down-regulated in non-small cell lung cancer. (PMID:19622307)
• Data show that restoration of GRIM-19 levels reestablishes the control over STAT3-dependent gene expression and tumor growth in vivo. (PMID:19642906)
• Loss of GRIM-19 is associated with invasion and metastasis of human gastric cancer. (PMID:20478305)
• Alternatively spliced GRIM-19 mRNA is associated with kidney cancer. (PMID:20505682)
• GRIM-19/CDKN2A synergistically suppressed cell cycle progression via inhibiting E2F1-driven gene expression. (PMID:20522552)
• Results identify a major role for the N terminus of GRIM-19 in mediating its tumor-suppressive actions. (PMID:20595633)
• reduced mRNA and protein levels in lung adenocarcinoma tissues (PMID:21040996)
• The expressions of survivin and GRIM-19 may be closely correlated with the pathogenesis of prostate cancer. (PMID:21351527)
• GRIM-19 function in cancer development (PMID:21664299)
• These data suggest that GRIM-19 can block E6/E6AP complex; and synergistically suppress cervical tumor growth with p53. (PMID:21765936)
• GRIM-19 expression was lower in gliomas & negatively correlated with malignancy. Downregulation enhanced cell proliferation & migration, but overexpression did the opposite. GRIM-19 exerts its role through the non-STAT3 signaling pathway. (PMID:21827581)
• GRIM-19 plays a critical role not only at the origin but also in the invasive progression of hepatocellular carcinoma. (PMID:22105514)
• GRIM-19 expression is closely correlated with histological grading and p-STAT3 in hepatocellular carcinoma (PMID:22492280)
• Our study found that GRIM-19 expression in lung cancer exhibits a relationship with the histological type and clinical stage (PMID:22573109)
• GRIM-19 inhibits the STAT3 signaling pathway and sensitizes gastric cancer cells to radiation. (PMID:23124042)
• import of the transcription factor STAT3 into mitochondria depends on GRIM-19, a component of the electron transport chain (PMID:23271731)
• Tumor-derived mutations in the gene associated with retinoid interferon-induced mortality (GRIM-19) disrupt its anti-signal transducer and activator of transcription 3 (STAT3) activity and promote oncogenesis (PMID:23386605)
• role in macrophage apoptosis induced by H5N1 virus (PMID:23529854)
• Downregulation of GRIM-19 promotes HIF1alpha synthesis. (PMID:23580587)
• Down-regulation of GRIM-19 is associated with STAT3 overexpression in breast carcinomas. (PMID:23618357)
• Expressions of GRIM-19, NDUFS3, and extracellular matrix elements are correlated with invasive capabilities of breast cancer cell lines. (PMID:23630608)
• GRIM-19 mutations are associated with oral squamous cell carcinoma. (PMID:23851499)
• silencing of survivin and over-expression of GRIM-19 can significantly inhibit the growth and induce the apoptosis of Hep-2 laryngeal cancer cells in vitro and in vivo. (PMID:24133585)
• GRIM-19 may regulate the differentiation of normal cervical tissue, and a decrease in GRIM-19 may be the result of HR-HPV infection, which in turn leads to the malignant transformation of the cells. (PMID:24690422)
• The GRIM-19 deficiency in the villus may be associated with missed abortion via increasing apoptosis and affecting angiogenesis. (PMID:25455534)
• GRIM-19 overexpression suppressed hepatocellular carcinoma (HCC) growth and downregulated AKT1 expression, suggesting that GRIM-19 might play a crucial role in hepatocarcinogenesis through negatively regulating the PI3K/AKT signaling pathway. (PMID:25550785)
• decreased GRIM-19 expression due to promoter hypermethylation may be important in head and neck carcinogenesis by promoting cell proliferation and regulating metabolic activity (PMID:25575809)
• We established here a correlation between the first mutation identified in the NDUFA13 gene, which induces Mitochondrial complex I instability and a severe but slowly evolving clinical presentation affecting the central nervous system. (PMID:25901006)
• High expression of GW112 in colorectal cancer tissues and reduced expression of GRIM-19 in colorectal cancer tissues may be associated with abnormal proliferation of cancer cells. (PMID:26011333)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
		ENSDARG00000098584
mus_musculus	Ndufa13	ENSMUSG00000036199
rattus_norvegicus	Ndufa13-ps1	ENSRNOG00000021688
rattus_norvegicus	Yjefn3	ENSRNOG00000039191
drosophila_melanogaster	ND-B16.6	FBGN0029868
caenorhabditis_elegans	ndua-13	WBGENE00016393

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 — Q9P0J0 (reviewed: Q9P0J0)

Alternative names: Cell death regulatory protein GRIM-19, Complex I-B16.6, Gene associated with retinoic and interferon-induced mortality 19 protein, NADH-ubiquinone oxidoreductase B16.6 subunit

All UniProt accessions (5): Q9P0J0, B4DEZ3, K7EJE1, K7EP87, U3KQP3

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. Involved in the interferon/all-trans-retinoic acid (IFN/RA) induced cell death. This apoptotic activity is inhibited by interaction with viral IRF1. Prevents the transactivation of STAT3 target genes. May play a role in CARD15-mediated innate mucosal responses and serve to regulate intestinal epithelial cell responses to microbes.

Subunit / interactions. Complex I is composed of 45 different subunits. Interacts with CARD15, but not with CARD4. Interacts with STAT3, but not with STAT1, STAT2 and STAT5A. Interacts with OLFM4. (Microbial infection) Interacts with HHV-8 IRF1, in the nucleus, with HPV-16 E6 and SV40 LT.

Subcellular location. Mitochondrion inner membrane. Nucleus.

Tissue specificity. Widely expressed, with highest expression in heart, skeletal muscle, liver, kidney and placenta. In intestinal mucosa, down-regulated in areas involved in Crohn disease and ulcerative colitis.

Disease relevance. Hurthle cell thyroid carcinoma (HCTC) [MIM:607464] A rare type of thyroid cancer accounting for only about 3-10% of all differentiated thyroid cancers. These neoplasms are considered a variant of follicular carcinoma of the thyroid and are referred to as follicular carcinoma, oxyphilic type. Disease susceptibility is associated with variants affecting the gene represented in this entry. Mitochondrial complex I deficiency, nuclear type 28 (MC1DN28) [MIM:618249] 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. MC1DN28 transmission pattern is consistent with autosomal recessive inheritance. The disease may be caused by variants affecting the gene represented in this entry.

Induction. By IFNB1/IFN-beta combined with all-trans-retinoic acid (ATRA).

Similarity. Belongs to the complex I NDUFA13 subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9P0J0-1	1	yes
Q9P0J0-2	2

RefSeq proteins (1): NP_057049* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009346	GRIM-19	Family

Pfam: PF06212

UniProt features (10 total): sequence variant 3, initiator methionine 1, chain 1, transmembrane region 1, region of interest 1, modified residue 1, splice variant 1, sequence conflict 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
5XTC	ELECTRON MICROSCOPY	3.7
5XTD	ELECTRON MICROSCOPY	3.7
5XTH	ELECTRON MICROSCOPY	3.9
5XTI	ELECTRON MICROSCOPY	17.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P0J0-F1	94.33	0.88

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): 2

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: 252 (showing top): GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, PAL_PRMT5_TARGETS_UP, MODULE_151, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, DITTMER_PTHLH_TARGETS_UP, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_RESPONSE_TO_INTERFERON_BETA

GO Biological Process (11): aerobic respiration (GO:0009060), mitochondrial respiratory chain complex I assembly (GO:0032981), cellular response to interferon-beta (GO:0035458), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), protein insertion into mitochondrial inner membrane (GO:0045039), positive regulation of protein catabolic process (GO:0045732), negative regulation of DNA-templated transcription (GO:0045892), cellular response to retinoic acid (GO:0071300), extrinsic apoptotic signaling pathway (GO:0097191), positive regulation of execution phase of apoptosis (GO:1900119), apoptotic process (GO:0006915)

GO Molecular Function (3): ATP binding (GO:0005524), endopeptidase activator activity (GO:0061133), protein binding (GO:0005515)

GO Cellular Component (9): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial membrane (GO:0031966), respiratory chain complex I (GO:0045271), respiratory chain complex (GO:0098803), nucleus (GO:0005634), 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
cellular anatomical structure	3
mitochondrion	2
apoptotic signaling pathway	2
execution phase of apoptosis	2
intracellular membrane-bounded organelle	2
cellular respiration	1
NADH dehydrogenase complex assembly	1
mitochondrial respiratory chain complex assembly	1
response to interferon-beta	1
cellular response to cytokine stimulus	1
oxidative phosphorylation	1
proton motive force-driven ATP synthesis	1
inner mitochondrial membrane organization	1
mitochondrial protein import pathway	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
response to retinoic acid	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
cell surface receptor signaling pathway	1
positive regulation of apoptotic process	1
regulation of execution phase of apoptosis	1
programmed cell death	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
endopeptidase activity	1
peptidase activator activity	1
endopeptidase regulator activity	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrial envelope	1

Protein interactions and networks

STRING

2880 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFA13	STAT3	P40763	910
NDUFA13	NDUFA3	O95167	904
NDUFA13	NDUFS3	O75489	891
NDUFA13	NDUFA9	Q16795	853
NDUFA13	NDUFA6	P56556	847
NDUFA13	NDUFA8	P51970	842
NDUFA13	NDUFA7	O95182	840
NDUFA13	NDUFS1	P28331	817
NDUFA13	NDUFV1	P49821	810
NDUFA13	NDUFS8	O00217	803
NDUFA13	NDUFA5	Q16718	799
NDUFA13	NDUFB6	O95139	791
NDUFA13	NDUFB7	P17568	783
NDUFA13	NDUFB11	Q9NX14	781
NDUFA13	NDUFS2	O75306	772

IntAct

127 interactions, top by confidence:

A	B	Type	Score
HTRA2	NDUFA13	psi-mi:“MI:0915”(physical association)	0.750
NDUFA13	HTRA2	psi-mi:“MI:0915”(physical association)	0.750
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
NDUFV2	NDUFS2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
HTT	NDUFA13	psi-mi:“MI:0915”(physical association)	0.670
LNPEP	CANX	psi-mi:“MI:0914”(association)	0.640
NDUFA13	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFAF4	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA9	NDUFS4	psi-mi:“MI:0914”(association)	0.640
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
NOD2	NDUFA13	psi-mi:“MI:0915”(physical association)	0.540

BioGRID (261): NDUFA13 (Affinity Capture-MS), NDUFA13 (Synthetic Growth Defect), NDUFA13 (Two-hybrid), NDUFA13 (Proximity Label-MS), NDUFA13 (Affinity Capture-MS), NDUFA13 (Affinity Capture-MS), NDUFA13 (Affinity Capture-MS), NDUFA13 (Affinity Capture-MS), NDUFAF1 (Affinity Capture-MS), TIMMDC1 (Affinity Capture-MS), ECSIT (Affinity Capture-MS), ACAD9 (Affinity Capture-MS), TMEM126B (Affinity Capture-MS), YME1L1 (Affinity Capture-MS), SLC25A6 (Affinity Capture-MS)

ESM2 similar proteins: A0A1N7SYS3, A1C8Z3, A5DM93, A6ZUI6, A7TFK6, B3LI56, C7GT24, C8Z970, O49313, P0CB94, P0CM84, P0CM85, P37267, P47081, P80977, Q02367, Q02854, Q0MQ88, Q0MQ89, Q0MQ90, Q0MQE0, Q0UIR3, Q1DME3, Q28GF4, Q29259, Q2PIY2, Q3T0E3, Q3UIU2, Q4I8P5, Q52ZA1, Q5ACH7, Q5AXJ9, Q5BKW8, Q5R7J0, Q68EV8, Q6BI17, Q6BY05, Q6CCF6, Q6CJX5, Q6CK73

Diamond homologs: O49313, Q0MQ88, Q0MQ89, Q0MQ90, Q4R6H1, Q86IZ2, Q8RWA7, Q95KV7, Q9ERS2, Q9P0J0

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NDUFA13	“form complex”	“NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I”	binding
TFEB	“up-regulates quantity by expression”	NDUFA13	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 114 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	20	43.0×	1e-25
Respiratory electron transport	21	25.9×	2e-22
Aerobic respiration and respiratory electron transport	19	21.8×	1e-18
Mitochondrial protein degradation	6	8.9×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	16	60.4×	3e-22
mitochondrial respiratory chain complex I assembly	12	51.9×	7e-16
proton motive force-driven mitochondrial ATP synthesis	16	44.4×	4e-20
aerobic respiration	16	41.7×	9e-20

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	26
Likely benign	18
Benign	2

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1693	NM_015965.7(NDUFA13):c.15G>C (p.Lys5Asn)	Pathogenic
983476	NM_015965.7(NDUFA13):c.194del (p.Phe65fs)	Pathogenic
983478	NM_015965.7(NDUFA13):c.107T>C (p.Leu36Pro)	Pathogenic
132643	NM_015965.7(NDUFA13):c.170G>A (p.Arg57His)	Likely pathogenic

SpliceAI

783 predictions. Top by Δscore:

Variant	Effect	Δscore
19:19516328:GTCGG:G	donor_gain	1.0000
19:19516330:CGGG:C	donor_loss	1.0000
19:19516331:GG:G	donor_gain	1.0000
19:19516331:GGGT:G	donor_loss	1.0000
19:19516332:GG:G	donor_gain	1.0000
19:19516333:G:GG	donor_gain	1.0000
19:19526256:CGCAG:C	donor_loss	1.0000
19:19526258:CAGGT:C	donor_loss	1.0000
19:19526259:AG:A	donor_loss	1.0000
19:19526259:AGGT:A	donor_loss	1.0000
19:19526260:GG:G	donor_loss	1.0000
19:19526260:GGT:G	donor_loss	1.0000
19:19526261:G:GA	donor_loss	1.0000
19:19526261:G:T	donor_loss	1.0000
19:19527350:G:GT	donor_gain	1.0000
19:19527696:CACA:C	acceptor_loss	1.0000
19:19527698:CA:C	acceptor_loss	1.0000
19:19527699:A:AC	acceptor_loss	1.0000
19:19527699:A:AG	acceptor_gain	1.0000
19:19527699:AG:A	acceptor_gain	1.0000
19:19527700:G:GG	acceptor_gain	1.0000
19:19527700:G:GT	acceptor_loss	1.0000
19:19527700:GG:G	acceptor_gain	1.0000
19:19527753:G:GT	donor_gain	1.0000
19:19527769:AGG:A	donor_loss	1.0000
19:19527770:GGT:G	donor_loss	1.0000
19:19527771:G:GA	donor_loss	1.0000
19:19527772:T:G	donor_loss	1.0000
19:19528987:CTCAG:C	donor_loss	1.0000
19:19528988:TCAGG:T	donor_loss	1.0000

AlphaMissense

933 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:19527349:G:C	R81P	0.996
19:19527336:G:C	A77P	0.995
19:19526257:G:C	R57P	0.993
19:19526197:C:A	A37D	0.992
19:19516262:G:C	Q8H	0.991
19:19516262:G:T	Q8H	0.991
19:19526202:G:A	G39R	0.988
19:19526202:G:C	G39R	0.988
19:19526209:G:A	G41E	0.988
19:19526203:G:A	G39E	0.986
19:19526208:G:A	G41R	0.986
19:19526208:G:C	G41R	0.986
19:19527310:G:C	R68P	0.985
19:19527319:T:C	L71P	0.985
19:19527749:G:A	M98I	0.985
19:19527749:G:C	M98I	0.985
19:19527749:G:T	M98I	0.985
19:19527767:G:C	W104C	0.985
19:19527767:G:T	W104C	0.985
19:19527306:G:C	A67P	0.984
19:19527765:T:A	W104R	0.983
19:19527765:T:C	W104R	0.983
19:19527727:T:C	L91P	0.979
19:19527283:G:C	R59P	0.977
19:19527286:T:C	L60P	0.977
19:19516263:G:C	D9H	0.976
19:19516306:G:C	R23P	0.976
19:19528022:T:C	F111L	0.975
19:19528024:C:A	F111L	0.975
19:19528024:C:G	F111L	0.975

dbSNP variants (sampled 300 via entrez): RS1000240763 (19:19518876 A>G), RS1000349247 (19:19525188 C>T), RS1000614648 (19:19520664 A>G), RS1000694496 (19:19520368 A>C), RS1001155495 (19:19527760 C>T), RS1001241530 (19:19521462 C>T), RS1001298943 (19:19514495 T>C), RS1001708485 (19:19515179 G>A,T), RS1001916701 (19:19517372 G>A,C), RS1002051209 (19:19525921 G>A,C), RS1002173624 (19:19520261 T>G), RS1002247188 (19:19520044 A>G), RS1002641616 (19:19515532 A>AC), RS1002770993 (19:19520544 C>G,T), RS1002811585 (19:19514254 G>A,C)

Disease associations

OMIM: gene MIM:609435 | disease phenotypes: MIM:618249, MIM:607464

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex I deficiency, nuclear type 28	Strong	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive
thyroid Hurthle cell carcinoma	Limited	Unknown

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Leigh syndrome	Moderate	AR
mitochondrial disease	Moderate	AR

Mondo (4): mitochondrial complex I deficiency, nuclear type 28 (MONDO:0032632), mitochondrial complex I deficiency (MONDO:0100133), thyroid Hurthle cell carcinoma (MONDO:0011836), (MONDO:0016815)

Orphanet (2): Isolated complex I deficiency (Orphanet:2609), Differentiated thyroid carcinoma (Orphanet:146)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000514	Slow saccadic eye movements
HP:0000543	Optic disc pallor
HP:0000648	Optic atrophy
HP:0000817	Reduced eye contact
HP:0001138	Optic neuropathy
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001272	Cerebellar atrophy
HP:0001508	Failure to thrive
HP:0002020	Gastroesophageal reflux
HP:0002061	Lower limb spasticity
HP:0002078	Truncal ataxia
HP:0002151	Increased circulating lactate concentration
HP:0002197	Generalized-onset seizure
HP:0002304	Akinesia
HP:0002421	Poor head control
HP:0002465	Poor speech
HP:0003348	Hyperalaninemia
HP:0003593	Infantile onset
HP:0003677	Slowly progressive
HP:0007256	Abnormal pyramidal sign
HP:0008936	Axial hypotonia
HP:0011923	Decreased activity of mitochondrial complex I
HP:0100660	Dyskinesia

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST002149_11	Schizophrenia	3.000000e-09
GCST002539_89	Schizophrenia	4.000000e-10
GCST004603_195	Platelet count	2.000000e-09
GCST006803_88	Schizophrenia	7.000000e-12
GCST007294_16	Body fat distribution (trunk fat ratio)	2.000000e-07
GCST007294_35	Body fat distribution (trunk fat ratio)	1.000000e-10
GCST007295_166	Body fat distribution (leg fat ratio)	2.000000e-11
GCST007295_22	Body fat distribution (leg fat ratio)	3.000000e-07
GCST008103_10	Bipolar disorder	1.000000e-09
GCST008115_2	Bipolar I disorder	3.000000e-09
GCST008116_4	Bipolar II disorder	4.000000e-06
GCST010002_52	Refractive error	4.000000e-29
GCST010703_335	Brain morphology (MOSTest)	3.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0004341	body fat distribution
EFO:0009963	bipolar I disorder
EFO:0009964	bipolar II disorder
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C537475	Mitochondrial complex I deficiency (supp.)
C536913	Thyroid cancer, Hurthle cell (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363065 (PROTEIN COMPLEX), CHEMBL4105781 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,305 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL483158	ALISERTIB	3	2,305

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

ChEMBL bioactivities

13 potent at pChembl≥5 of 23 total, top 13 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.23	Kd	5.854	nM	CHEMBL5653589
8.23	ED50	5.854	nM	CHEMBL5653589
6.67	Kd	211.5	nM	CHEMBL3752910
6.67	ED50	211.5	nM	CHEMBL3752910
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
5.41	Kd	3920	nM	ALISERTIB
5.31	IC50	4900	nM	(+)-9’-ISOVALEROXYLARICIRESINOL
5.04	IC50	9100	nM	(+)-9’-ISOVALEROXYLARICIRESINOL

PubChem BioAssay actives

11 with measured affinity, of 258 total; 7 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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148839: Binding affinity to human NDUFA13 incubated for 45 mins by Kinobead based pull down assay	kd	0.0059	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148839: Binding affinity to human NDUFA13 incubated for 45 mins by Kinobead based pull down assay	kd	0.2115	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
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] octanoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	3.0800	uM
4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid	1425084: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	3.9200	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
bisphenol A	increases expression, affects expression	3
sodium arsenite	decreases expression, increases expression	2
Valproic Acid	increases methylation, affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
tris(2-butoxyethyl) phosphate	increases abundance, decreases expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	decreases expression	1
azoxystrobin	increases expression	1
oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine	affects expression, increases reaction	1
pyrimidifen	increases expression	1
ICG 001	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects reaction, decreases phosphorylation, increases expression	1
Temozolomide	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Atrazine	decreases expression	1
Vehicle Emissions	affects expression, increases reaction	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases abundance, increases expression	1
Diuron	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Flame Retardants	increases abundance, decreases expression	1
Hydralazine	increases expression, affects cotreatment	1

ChEMBL screening assays

6 unique, capped per target: 6 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

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1YC	Abcam HeLa NDUFA13 KO	Cancer cell line	Female

Clinical trials (associated diseases)

8 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)
NCT01811212	PHASE2	COMPLETED	Cabozantinib-S-Malate in Treating Patients With Refractory Thyroid Cancer
NCT02143726	PHASE2	ACTIVE_NOT_RECRUITING	Sorafenib Tosylate With or Without Everolimus in Treating Patients With Advanced, Radioactive Iodine Refractory Hurthle Cell Thyroid Cancer
NCT02973997	PHASE2	COMPLETED	Lenvatinib and Pembrolizumab in Differentiated Thyroid Cancers (DTC)
NCT05410821	PHASE1	COMPLETED	Evaluation of 177Lu-DOTA-EB-FAPI in Patients With Metastatic Radioactive Iodine Refractory Thyroid Cancer
NCT01208051	PHASE1/PHASE2	COMPLETED	Cediranib Maleate With or Without Lenalidomide for the Treatment of Thyroid Cancer
NCT00001160	Not specified	RECRUITING	Studies on Tumors of the Thyroid
NCT01441154	Not specified	COMPLETED	Metabolic Effects of Synthetic Thyroid Hormone for Thyroid Cancer Treatment