mitochondrial complex I deficiency, nuclear type 1

Summary

mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224) is a disease caused by variants in FOXRED1 and NDUFS4, with 27 cohort genes and 1 clinical trial. The dominant Reactome pathway is Complex I biogenesis (23 cohort genes). Top therapeutic interventions include elamipretide.

At a glance

• Causal genes: FOXRED1 (GenCC Strong), NDUFS4 (GenCC Strong)
• Cohort genes: 27
• ClinVar variants: 799
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex I deficiency, nuclear type 1
Mondo ID	MONDO:0100224
OMIM	252010
DOID	DOID:0112074
GARD	0015201
Is cancer (heuristic)	no

Also known as: MC1DN1 · mitochondrial complex 1 deficiency · mitochondrial complex I deficiency · mitochondrial complex I deficiency, nuclear type 1 · mitochondrial NADH dehydrogenase component of Complex I, deficiency of · NADH-coenzyme Q reductase deficiency · NADH:Q(1) oxidoreductase deficiency

Data availability: 799 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › congenital structural myopathy › inborn mitochondrial myopathy › mitochondrial complex I deficiency, nuclear type 1

Related subtypes (23): myopathy, lactic acidosis, and sideroblastic anemia, mitochondrial encephalomyopathy, progressive external ophthalmoplegia, mitochondrial myopathy with a defect in mitochondrial-protein transport, Barth syndrome, mitochondrial myopathy with diabetes, mitochondrial myopathy with reversible cytochrome C oxidase deficiency, lethal infantile mitochondrial myopathy, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, mitochondrial trifunctional protein deficiency, adenosine monophosphate deaminase deficiency, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, autosomal dominant mitochondrial myopathy with exercise intolerance, fatal infantile encephalocardiomyopathy, mitochondrial myopathy-lactic acidosis-deafness syndrome, mitochondrial neurogastrointestinal encephalomyopathy, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, maternally-inherited progressive external ophthalmoplegia, mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy, mitochondrial complex II deficiency, nuclear type, mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome, X-linked recessive mitochondrial myopathy, COX deficiency, benign infantile mitochondrial myopathy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

280 uncertain significance, 176 conflicting classifications of pathogenicity, 67 benign, 29 benign/likely benign, 21 likely pathogenic, 12 pathogenic/likely pathogenic, 9 pathogenic, 6 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
419231	NM_174889.5(NDUFAF2):c.114C>G (p.Tyr38Ter)	ERCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
14056	NM_007103.4(NDUFV1):c.1268C>T (p.Thr423Met)	LOC126861242	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
419230	NM_007103.4(NDUFV1):c.1156C>T (p.Arg386Cys)	LOC126861242	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676991	NM_002495.4(NDUFS4):c.26del (p.Val9fs)	LOC129993885	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6890	NM_002495.4(NDUFS4):c.44G>A (p.Trp15Ter)	LOC129993885	Pathogenic	no assertion criteria provided
1594	NM_174889.5(NDUFAF2):c.139C>T (p.Arg47Ter)	NDUFAF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265061	NM_024120.5(NDUFAF5):c.327G>C (p.Lys109Asn)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190302	NM_001135998.3(NDUFB11):c.262C>T (p.Arg88Ter)	NDUFB11	Pathogenic	criteria provided, multiple submitters, no conflicts
626277	NM_005006.7(NDUFS1):c.64C>T (p.Arg22Ter)	NDUFS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1693584	NM_002495.4(NDUFS4):c.350+1G>A	NDUFS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203649	NM_002495.4(NDUFS4):c.393dup (p.Glu132fs)	NDUFS4	Pathogenic	criteria provided, multiple submitters, no conflicts
2231090	NM_002495.4(NDUFS4):c.319_322del (p.Trp107fs)	NDUFS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445773	NM_002495.4(NDUFS4):c.221del (p.Thr74fs)	NDUFS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40257	NM_002495.4(NDUFS4):c.462del (p.Lys154fs)	NDUFS4	Pathogenic	criteria provided, multiple submitters, no conflicts
496165	NM_002495.4(NDUFS4):c.99-1G>A	NDUFS4	Pathogenic	criteria provided, multiple submitters, no conflicts
587577	NM_002495.4(NDUFS4):c.355G>C (p.Asp119His)	NDUFS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6887	NM_002495.4(NDUFS4):c.466_470dup (p.Lys158fs)	NDUFS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6888	NM_002495.4(NDUFS4):c.291del (p.Lys96_Trp97insTer)	NDUFS4	Pathogenic	criteria provided, multiple submitters, no conflicts
6889	NM_002495.4(NDUFS4):c.316C>T (p.Arg106Ter)	NDUFS4	Pathogenic	criteria provided, multiple submitters, no conflicts
372716	NM_007103.4(NDUFV1):c.1162+4A>C	NDUFV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1032805	NM_018480.7(TMEM126B):c.320_321del (p.Tyr107fs)	TMEM126B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3239848	NM_002495.4(NDUFS4):c.20C>G (p.Ser7Ter)	LOC129993885	Likely pathogenic	criteria provided, single submitter
3592716	NM_002495.4(NDUFS4):c.27_32delinsCCTGC (p.Gln12fs)	LOC129993885	Likely pathogenic	criteria provided, single submitter
626278	NM_005006.7(NDUFS1):c.845A>G (p.Asn282Ser)	NDUFS1	Likely pathogenic	no assertion criteria provided
2502291	NM_002495.4(NDUFS4):c.351-1G>C	NDUFS4	Likely pathogenic	criteria provided, single submitter
2671778	NM_002495.4(NDUFS4):c.351-2A>G	NDUFS4	Likely pathogenic	criteria provided, single submitter
2676990	NM_002495.4(NDUFS4):c.415G>T (p.Glu139Ter)	NDUFS4	Likely pathogenic	criteria provided, single submitter
2676992	NM_002495.4(NDUFS4):c.424+2T>A	NDUFS4	Likely pathogenic	criteria provided, single submitter
2676993	NM_002495.4(NDUFS4):c.235del (p.Ile79fs)	NDUFS4	Likely pathogenic	criteria provided, single submitter
2676994	NM_002495.4(NDUFS4):c.424G>T (p.Gly142Ter)	NDUFS4	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 29 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FOXRED1	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 19	7
NDUFS4	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 1	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOXRED1	Orphanet:2609	Isolated complex I deficiency
NDUFS4	Orphanet:2609	Isolated complex I deficiency
TIMMDC1	Orphanet:2609	Isolated complex I deficiency
NDUFAF5	Orphanet:2609	Isolated complex I deficiency
NDUFAF1	Orphanet:2609	Isolated complex I deficiency
NUBPL	Orphanet:2609	Isolated complex I deficiency
NDUFA11	Orphanet:2609	Isolated complex I deficiency
NDUFB11	Orphanet:2556	Microphthalmia with linear skin defects syndrome
NDUFB11	Orphanet:2609	Isolated complex I deficiency
NDUFAF4	Orphanet:2609	Isolated complex I deficiency
NDUFAF2	Orphanet:2609	Isolated complex I deficiency
NDUFAF6	Orphanet:3337	Primary Fanconi renotubular syndrome
NDUFAF3	Orphanet:2609	Isolated complex I deficiency
TMEM126B	Orphanet:2609	Isolated complex I deficiency
ERCC8	Orphanet:178338	UV-sensitive syndrome
ERCC8	Orphanet:90321	Cockayne syndrome type 1
ERCC8	Orphanet:90322	Cockayne syndrome type 2
ERCC8	Orphanet:90324	Cockayne syndrome type 3
NDUFA2	Orphanet:85136	Cystic leukoencephalopathy without megalencephaly
NDUFS1	Orphanet:2609	Isolated complex I deficiency
NDUFS2	Orphanet:104	Leber hereditary optic neuropathy
NDUFS2	Orphanet:2609	Isolated complex I deficiency
NDUFS3	Orphanet:2609	Isolated complex I deficiency
NDUFS6	Orphanet:2609	Isolated complex I deficiency
NDUFS7	Orphanet:2609	Isolated complex I deficiency
NDUFS8	Orphanet:2609	Isolated complex I deficiency
NDUFV1	Orphanet:2609	Isolated complex I deficiency
NDUFV2	Orphanet:139447	Progressive cavitating leukoencephalopathy
NDUFV2	Orphanet:2609	Isolated complex I deficiency

Cohort genes → proteins

27 cohort genes, 26 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	27

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FOXRED1	HGNC:26927	ENSG00000110074	Q96CU9	FAD-dependent oxidoreductase domain-containing protein 1	gencc,clinvar
NDUFS4	HGNC:7711	ENSG00000164258	O43181	NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial	gencc,clinvar
TIMMDC1	HGNC:1321	ENSG00000113845	Q9NPL8	Complex I assembly factor TIMMDC1, mitochondrial	clinvar
MRPL36	HGNC:14490	ENSG00000171421	Q9P0J6	Large ribosomal subunit protein bL36m	clinvar
NDUFAF5	HGNC:15899	ENSG00000101247	Q5TEU4	Arginine-hydroxylase NDUFAF5, mitochondrial	clinvar
NDUFAF1	HGNC:18828	ENSG00000137806	Q9Y375	Complex I intermediate-associated protein 30, mitochondrial	clinvar
NUBPL	HGNC:20278	ENSG00000151413	Q8TB37	Iron-sulfur cluster transfer protein NUBPL	clinvar
NDUFA11	HGNC:20371	ENSG00000174886	Q86Y39	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11	clinvar
NDUFB11	HGNC:20372	ENSG00000147123	Q9NX14	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial	clinvar
NDUFAF4	HGNC:21034	ENSG00000123545	Q9P032	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 4	clinvar
NDUFAF2	HGNC:28086	ENSG00000164182	Q8N183	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 2	clinvar
NDUFAF6	HGNC:28625	ENSG00000156170	Q330K2	NADH dehydrogenase (ubiquinone) complex I, assembly factor 6	clinvar
TMCO6	HGNC:28814	ENSG00000113119	Q96DC7	Transmembrane and coiled-coil domain-containing protein 6	clinvar
NDUFAF3	HGNC:29918	ENSG00000178057	Q9BU61	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3	clinvar
TMEM126B	HGNC:30883	ENSG00000171204	Q8IUX1	Complex I assembly factor TMEM126B, mitochondrial	clinvar
ERCC8	HGNC:3439	ENSG00000049167	Q13216	DNA excision repair protein ERCC-8	clinvar
NDUFV2-AS1	HGNC:50826	ENSG00000266053		NDUFV2 antisense RNA 1	clinvar
NDUFA10	HGNC:7684	ENSG00000130414	O95299	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial	clinvar
NDUFA2	HGNC:7685	ENSG00000131495	O43678	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2	clinvar
NDUFS1	HGNC:7707	ENSG00000023228	P28331	NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial	clinvar
NDUFS2	HGNC:7708	ENSG00000158864	O75306	NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial	clinvar
NDUFS3	HGNC:7710	ENSG00000213619	O75489	NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial	clinvar
NDUFS6	HGNC:7713	ENSG00000145494	O75380	NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial	clinvar
NDUFS7	HGNC:7714	ENSG00000115286	O75251	NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial	clinvar
NDUFS8	HGNC:7715	ENSG00000110717	O00217	NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial	clinvar
NDUFV1	HGNC:7716	ENSG00000167792	P49821	NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial	clinvar
NDUFV2	HGNC:7717	ENSG00000178127	P19404	NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FOXRED1	FAD-dependent oxidoreductase domain-containing protein 1	Required for the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I).
NDUFS4	NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
TIMMDC1	Complex I assembly factor TIMMDC1, mitochondrial	Chaperone protein involved in the assembly of the mitochondrial NADH:ubiquinone oxidoreductase complex (complex I).
NDUFAF5	Arginine-hydroxylase NDUFAF5, mitochondrial	Arginine hydroxylase that mediates hydroxylation of ‘Arg-111’ of NDUFS7 and is involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1) at early stages.
NDUFAF1	Complex I intermediate-associated protein 30, mitochondrial	As part of the MCIA complex, involved in the assembly of the mitochondrial complex I.
NUBPL	Iron-sulfur cluster transfer protein NUBPL	Iron-sulfur cluster transfer protein involved in the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I).
NDUFA11	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
NDUFB11	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
NDUFAF4	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 4	Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I).
NDUFAF2	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 2	Acts as a molecular chaperone for mitochondrial complex I assembly.
NDUFAF6	NADH dehydrogenase (ubiquinone) complex I, assembly factor 6	Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I) at early stages.
NDUFAF3	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3	Essential factor for the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I).
TMEM126B	Complex I assembly factor TMEM126B, mitochondrial	As part of the MCIA complex, involved in the assembly of the mitochondrial complex I.
ERCC8	DNA excision repair protein ERCC-8	Substrate-recognition component of the CSA complex, a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex, involved in transcription-coupled nucleotide excision repair (TC-NER), a process during which RNA polymerase II-blocking lesio…
NDUFA10	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
NDUFA2	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
NDUFS1	NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial	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.
NDUFS2	NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial	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.
NDUFS3	NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial	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.
NDUFS6	NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
NDUFS7	NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial	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.
NDUFS8	NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial	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.
NDUFV1	NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial	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.
NDUFV2	NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial	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.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 24 · Druggable fraction: 0.04

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	24	1.6×	1e-03
Kinase	1	1.0×	0.969
Scaffold/PPI	1	0.6×	0.969
Transcription factor	1	0.3×	0.969

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FOXRED1	Other/Unknown	no		FAD-dep_OxRdtase, FAD/NAD-bd_sf
NDUFS4	Other/Unknown	no		NADH_UbQ_FeS_4_mit-like, NDUFS4-like_sf
TIMMDC1	Other/Unknown	no		TIMMDC1
MRPL36	Other/Unknown	no		Ribosomal_bL36, Ribosomal_bL36_sp, Mitoribosomal_bL36m
NDUFAF5	Other/Unknown	no		Methyltransf_11, SAM-dependent_MTases_sf, Malonyl-ACP_OMT
NDUFAF1	Other/Unknown	no		Galactose-bd-like_sf, NADH-UbQ_OxRdtase-assoc_prot30, NDUFAF1
NUBPL	Other/Unknown	no		Mrp-like_CS, Mrp/NBP35_ATP-bd, P-loop_NTPase
NDUFA11	Other/Unknown	no		NDUFA11
NDUFB11	Other/Unknown	no		NADH_UbQ_OxRdtase_ESSS_su
NDUFAF4	Other/Unknown	no		NDUFAF4
NDUFAF2	Other/Unknown	no		NDUFA12, ComplexI_NDUFA12
NDUFAF6	Other/Unknown	no		Squ/phyt_synthse, Isoprenoid_synthase_dom_sf
TMCO6	Other/Unknown	no		Armadillo, Importin-a_IBB, ARM-like
NDUFAF3	Other/Unknown	no		NDUFAF3/AAMDC, NDUF3, MTH938-like_sf
TMEM126B	Other/Unknown	no		TMEM126
ERCC8	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
NDUFV2-AS1	Other/Unknown	no
NDUFA10	Kinase	yes		NDUFA10, P-loop_NTPase, DNK_dom
NDUFA2	Other/Unknown	no		Ribosomal_mL43/mS25/NADH_DH, NADH_Ub_cplx-1_asu_su-2, Thioredoxin-like_sf
NDUFS1	Other/Unknown	no		NADH_UbQ_OxRdtase_75kDa_su_CS, 2Fe-2S_ferredoxin-type, Mopterin_OxRdtase
NDUFS2	Other/Unknown	no		NADH_Q_OxRdtase_suD, NADH_UbQ_OxRdtase_49kDa_CS, NDH1_su_D/H
NDUFS3	Other/Unknown	no		NADH_UbQ_OxRdtase_30kDa_su, NADH_DH_suC, NADH_UbQ_OxRdtase_CS
NDUFS6	Transcription factor	no		NDUFS6, Znf_CHCC
NDUFS7	Other/Unknown	no		NADH_UbQ_OxRdtase-like_20kDa, NADH_UQ_OxRdtase_20Kd_su
NDUFS8	Other/Unknown	no		NADH_quinone_OxRdtase_chainI, 4Fe4S_Fe-S-bd, 4Fe4S_Fe_S_CS
NDUFV1	Other/Unknown	no		NADH-UbQ_OxRdtase_51kDa_CS, NADH-UbQ_OxRdtase_suF, Nuo51_FMN-bd
NDUFV2	Other/Unknown	no		NuoE-like, Thioredoxin-like_sf, NuoE_N

Expression context

Cohort genes with no expression data: 0.

24 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	27
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	12
gastrocnemius	6
hindlimb stylopod muscle	5
calcaneal tendon	3
left ventricle myocardium	3
right adrenal gland	3
adrenal tissue	3
right hemisphere of cerebellum	2
cardiac muscle of right atrium	2
pancreatic ductal cell	2
tibialis anterior	2
right atrium auricular region	2
skeletal muscle tissue of biceps brachii	2
heart right ventricle	2
left testis	2
right testis	2
heart left ventricle	2
cerebellar cortex	1
cerebellar hemisphere	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOXRED1	232	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
NDUFS4	294	ubiquitous	marker	calcaneal tendon, skeletal muscle tissue of rectus abdominis, hindlimb stylopod muscle
TIMMDC1	259	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
MRPL36	255	ubiquitous	marker	pancreatic ductal cell, tibialis anterior, left ventricle myocardium
NDUFAF5	261	ubiquitous	marker	apex of heart, right atrium auricular region, hindlimb stylopod muscle
NDUFAF1	281	ubiquitous	marker	apex of heart, gastrocnemius, right adrenal gland
NUBPL	267	ubiquitous	marker	calcaneal tendon, adrenal tissue, skeletal muscle tissue of biceps brachii
NDUFA11	260	ubiquitous	marker	pancreatic ductal cell, cardiac muscle of right atrium, left ventricle myocardium
NDUFB11	287	ubiquitous	marker	apex of heart, hindlimb stylopod muscle, gastrocnemius
NDUFAF4	286	ubiquitous	marker	pons, lateral nuclear group of thalamus, heart right ventricle
NDUFAF2	139	ubiquitous	marker	calcaneal tendon, lower esophagus muscularis layer, gastrocnemius
NDUFAF6	242	ubiquitous	marker	right uterine tube, tibialis anterior, deltoid
TMCO6	216	ubiquitous	yes	sural nerve, right lobe of liver, right adrenal gland
NDUFAF3	280	ubiquitous	marker	left testis, right testis, apex of heart
TMEM126B	283	ubiquitous	marker	pigmented layer of retina, C1 segment of cervical spinal cord, islet of Langerhans
ERCC8	218	ubiquitous	yes	adrenal tissue, ventricular zone, primordial germ cell in gonad
NDUFV2-AS1	186	broad	yes	sperm, left testis, right testis
NDUFA10	291	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
NDUFA2	300	ubiquitous	marker	biceps brachii, heart right ventricle, skeletal muscle tissue of biceps brachii
NDUFS1	142	ubiquitous	marker	corpus callosum, skeletal muscle tissue, adrenal tissue
NDUFS2	292	ubiquitous	marker	apex of heart, gastrocnemius, heart left ventricle
NDUFS3	140	ubiquitous	marker	putamen, mucosa of transverse colon, apex of heart
NDUFS6	295	ubiquitous	marker	tendon of biceps brachii, apex of heart, right atrium auricular region
NDUFS7	286	ubiquitous	marker	hindlimb stylopod muscle, apex of heart, gastrocnemius
NDUFS8	294	ubiquitous	marker	apex of heart, right adrenal gland, right adrenal gland cortex
NDUFV1	292	ubiquitous	marker	apex of heart, right hemisphere of cerebellum, metanephros cortex
NDUFV2	137	ubiquitous	marker	apex of heart, gastrocnemius, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 155.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFS3	5,461
NDUFS8	5,298
NDUFS2	4,412
NDUFV1	3,982
NDUFV2	3,918
NDUFS1	3,899
NDUFS7	3,621
NDUFA2	3,304
MRPL36	2,977
NDUFS6	2,955

Intra-cohort edges

A	B	Sources
FOXRED1	NDUFAF1	string_interaction
FOXRED1	NDUFAF2	string_interaction
FOXRED1	NDUFAF3	string_interaction
FOXRED1	NDUFAF4	string_interaction
FOXRED1	NDUFAF5	string_interaction
FOXRED1	NDUFAF6	string_interaction
FOXRED1	NDUFS4	string_interaction
FOXRED1	NDUFS7	string_interaction
FOXRED1	NUBPL	string_interaction
FOXRED1	TIMMDC1	string_interaction
FOXRED1	TMEM126B	string_interaction
NDUFA10	NDUFA11	biogrid_interaction, intact
NDUFA10	NDUFA2	intact, string_interaction
NDUFA10	NDUFAF5	biogrid_interaction
NDUFA10	NDUFS1	string_interaction
NDUFA10	NDUFS2	biogrid_interaction, string_interaction
NDUFA10	NDUFS3	intact, string_interaction
NDUFA10	NDUFS6	intact
NDUFA10	NDUFS8	string_interaction
NDUFA10	NDUFV1	biogrid_interaction, string_interaction
NDUFA10	NDUFV2	intact
NDUFA11	NDUFA2	biogrid_interaction, intact, string_interaction
NDUFA11	NDUFAF4	string_interaction
NDUFA11	NDUFB11	intact
NDUFA11	NDUFS1	biogrid_interaction, string_interaction
NDUFA11	NDUFS2	biogrid_interaction, string_interaction
NDUFA11	NDUFS3	intact
NDUFA11	NDUFS4	biogrid_interaction, intact
NDUFA11	NDUFS6	string_interaction
NDUFA11	NDUFS7	string_interaction
NDUFA11	NDUFS8	intact, string_interaction
NDUFA11	NDUFV1	biogrid_interaction, string_interaction
NDUFA11	NDUFV2	biogrid_interaction, string_interaction
NDUFA2	NDUFAF2	string_interaction
NDUFA2	NDUFS1	string_interaction
NDUFA2	NDUFS3	biogrid_interaction, intact
NDUFA2	NDUFS4	biogrid_interaction, string_interaction
NDUFA2	NDUFS6	intact, string_interaction
NDUFA2	NDUFS8	intact, string_interaction
NDUFA2	NDUFV1	biogrid_interaction, string_interaction
NDUFA2	NDUFV2	biogrid_interaction, intact, string_interaction
NDUFAF1	NDUFAF2	string_interaction
NDUFAF1	NDUFAF3	biogrid_interaction, intact, string_interaction
NDUFAF1	NDUFAF4	biogrid_interaction, intact, string_interaction
NDUFAF1	NDUFAF5	string_interaction
NDUFAF1	NDUFAF6	string_interaction
NDUFAF1	NDUFB11	biogrid_interaction, intact
NDUFAF1	NDUFS1	biogrid_interaction, intact
NDUFAF1	NDUFS3	biogrid_interaction, intact
NDUFAF1	NDUFS7	intact, string_interaction

Structural data

PDB: 15 · AlphaFold-only: 11 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPL36	Q9P0J6	73
ERCC8	Q13216	16
NDUFA2	O43678	8
NDUFS2	O75306	8
NDUFS4	O43181	7
NDUFA11	Q86Y39	7
NDUFB11	Q9NX14	7
NDUFS1	P28331	7
NDUFS3	O75489	7
NDUFS6	O75380	7
NDUFS7	O75251	7
NDUFS8	O00217	7
NDUFV1	P49821	7
NDUFV2	P19404	7
NDUFA10	O95299	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FOXRED1	Q96CU9	90.12
NDUFAF6	Q330K2	87.70
TMCO6	Q96DC7	87.22
NDUFAF5	Q5TEU4	85.43
NUBPL	Q8TB37	85.40
NDUFAF4	Q9P032	83.37
TMEM126B	Q8IUX1	82.06
NDUFAF3	Q9BU61	79.02
NDUFAF2	Q8N183	78.98
NDUFAF1	Q9Y375	73.37
TIMMDC1	Q9NPL8	72.08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 27 evidence-associated genes (25 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 25 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Complex I biogenesis	23	152.3×	1e-49	FOXRED1, NDUFS4, TIMMDC1, NDUFAF5, NDUFAF1, NUBPL, NDUFA11, NDUFB11 (+15 more)
Respiratory electron transport	20	76.1×	3e-35	NDUFS4, TIMMDC1, NDUFAF5, NDUFA11, NDUFB11, NDUFAF4, NDUFAF2, NDUFAF6 (+12 more)
Aerobic respiration and respiratory electron transport	20	70.8×	9e-35	NDUFS4, TIMMDC1, NDUFAF5, NDUFA11, NDUFB11, NDUFAF4, NDUFAF2, NDUFAF6 (+12 more)
Metabolism	20	9.3×	8e-17	NDUFS4, TIMMDC1, NDUFAF5, NDUFA11, NDUFB11, NDUFAF4, NDUFAF2, NDUFAF6 (+12 more)
Mitochondrial protein degradation	4	18.3×	3e-04	NDUFA2, NDUFS1, NDUFS3, NDUFV1
Metabolism of proteins	5	2.5×	0.171	MRPL36, NDUFA2, NDUFS1, NDUFS3, NDUFV1
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	1	10.6×	0.271	ERCC8
Formation of TC-NER Pre-Incision Complex	1	8.5×	0.271	ERCC8
Gap-filling DNA repair synthesis and ligation in TC-NER	1	7.1×	0.271	ERCC8
Dual incision in TC-NER	1	6.9×	0.271	ERCC8
RHOG GTPase cycle	1	5.9×	0.271	NDUFS3
Mitochondrial translation	1	5.5×	0.271	MRPL36
Mitochondrial translation initiation	1	5.1×	0.271	MRPL36
Mitochondrial translation elongation	1	5.1×	0.271	MRPL36
Mitochondrial ribosome-associated quality control	1	4.9×	0.271	MRPL36
Mitochondrial translation termination	1	4.4×	0.281	MRPL36
Translation	1	2.5×	0.419	MRPL36
RHO GTPase cycle	1	2.4×	0.419	NDUFS3
Neddylation	1	1.9×	0.479	ERCC8
Signaling by Rho GTPases	1	1.4×	0.557	NDUFS3
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	1.3×	0.557	NDUFS3
Signal Transduction	1	0.4×	0.925	NDUFS3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 26 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial respiratory chain complex I assembly	17	268.8×	1e-38	FOXRED1, NDUFS4, TIMMDC1, NDUFAF5, NDUFAF1, NUBPL, NDUFAF4, NDUFAF2 (+9 more)
mitochondrial electron transport, NADH to ubiquinone	13	179.3×	3e-26	NDUFS4, NDUFAF1, NDUFA11, NDUFA10, NDUFA2, NDUFS1, NDUFS2, NDUFS3 (+5 more)
proton motive force-driven mitochondrial ATP synthesis	13	131.7×	2e-24	NDUFS4, NDUFA11, NDUFB11, NDUFA10, NDUFA2, NDUFS1, NDUFS2, NDUFS3 (+5 more)
aerobic respiration	13	123.9×	3e-24	NDUFS4, NDUFA11, NDUFB11, NDUFA10, NDUFA2, NDUFS1, NDUFS2, NDUFS3 (+5 more)
reactive oxygen species metabolic process	3	54.0×	3e-04	NDUFS4, NDUFS3, NDUFS6
mitochondrial ATP synthesis coupled electron transport	2	144.0×	8e-04	NDUFS2, NDUFV1
regulation of transcription-coupled nucleotide-excision repair	1	648.1×	0.013	ERCC8
mesenchymal stem cell differentiation	1	324.1×	0.020	NDUFS6
mesenchymal stem cell proliferation	1	324.1×	0.020	NDUFS6
electron transport coupled proton transport	1	162.0×	0.032	NDUFS7
cellular response to oxygen levels	1	162.0×	0.032	NDUFS2
gliogenesis	1	108.0×	0.045	NDUFS2
reproductive system development	1	92.6×	0.048	NDUFS6
stem cell division	1	72.0×	0.056	NDUFS6
negative regulation of insulin secretion involved in cellular response to glucose stimulus	1	64.8×	0.056	NDUFAF2
double-strand break repair via classical nonhomologous end joining	1	64.8×	0.056	ERCC8
single strand break repair	1	54.0×	0.059	ERCC8
circulatory system development	1	54.0×	0.059	NDUFS6
transcription-coupled nucleotide-excision repair	1	46.3×	0.065	ERCC8
regulation of protein phosphorylation	1	43.2×	0.066	NDUFS4
response to X-ray	1	34.1×	0.076	ERCC8
cardiac muscle tissue development	1	34.1×	0.076	NDUFV2
response to auditory stimulus	1	28.2×	0.088	ERCC8
chaperone-mediated protein complex assembly	1	27.0×	0.088	NDUFAF1
neural precursor cell proliferation	1	25.9×	0.088	NDUFS2
iron-sulfur cluster assembly	1	23.1×	0.094	NUBPL
blastocyst hatching	1	20.9×	0.097	NDUFA2
regulation of mitochondrial membrane potential	1	20.9×	0.097	NDUFS6
response to cAMP	1	19.6×	0.099	NDUFS4
response to food	1	19.1×	0.099	TMEM126B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 27

Druggability breadth: 17 of 27 evidence-associated genes (63%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FOXRED1	0	0
NDUFS4	0	0
TIMMDC1	0	0
MRPL36	0	0
NDUFAF5	0	0
NDUFAF1	0	0
NUBPL	0	0
NDUFA11	0	0
NDUFB11	0	0
NDUFAF4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NDUFS2	11	Binding:10, Functional:1
NDUFAF4	5	Binding:5
NDUFAF2	5	Binding:5
NDUFA10	5	Binding:5
NDUFS1	5	Binding:5
NDUFS3	5	Binding:5
NDUFS6	5	Binding:5
NDUFS7	5	Binding:5
NDUFV1	5	Binding:5
NDUFV2	5	Binding:5
NDUFS4	4	Binding:4
NDUFAF1	4	Binding:4
NDUFA11	4	Binding:4
NDUFB11	4	Binding:4
NDUFAF3	4	Binding:4
NDUFA2	4	Binding:4
NDUFS8	4	Binding:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 26; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	NDUFA10
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	26	FOXRED1, NDUFS4, TIMMDC1, MRPL36, NDUFAF5, NDUFAF1, NUBPL, NDUFA11, NDUFB11, NDUFAF4 (+16 more)

Undrugged target profiles

27 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FOXRED1	0	—
NDUFS4	4	—
TIMMDC1	0	—
MRPL36	0	—
NDUFAF5	0	—
NDUFAF1	4	—
NUBPL	0	—
NDUFA11	4	—
NDUFB11	4	—
NDUFAF4	5	—
NDUFAF2	5	—
NDUFAF6	0	—
TMCO6	0	—
NDUFAF3	4	—
TMEM126B	0	—
ERCC8	0	—
NDUFV2-AS1	0	—
NDUFA10	5	—
NDUFA2	4	—
NDUFS1	5	—
NDUFS2	11	—
NDUFS3	5	—
NDUFS6	5	—
NDUFS7	5	—
NDUFS8	4	—
NDUFV1	5	—
NDUFV2	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1

Top trials by phase / activity

NCT	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)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ELAMIPRETIDE	3	1