mitochondrial complex I deficiency

Summary

mitochondrial complex I deficiency (MONDO:0100133) is a disease with 38 cohort genes and 1 clinical trial. The dominant Reactome pathway is Complex I biogenesis (34 cohort genes). Top therapeutic interventions include elamipretide.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 38
• ClinVar variants: 202
• Phenotypes (HPO): 37
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0011923	Decreased activity of mitochondrial complex I	Obligate (100%)
HP:0000114	Proximal tubulopathy	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0000486	Strabismus	Very frequent (80-99%)
HP:0000508	Ptosis	Very frequent (80-99%)
HP:0000543	Optic disc pallor	Very frequent (80-99%)
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0000817	Reduced eye contact	Very frequent (80-99%)
HP:0001138	Optic neuropathy	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001254	Lethargy	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001298	Encephalopathy	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0001639	Hypertrophic cardiomyopathy	Very frequent (80-99%)
HP:0001943	Hypoglycemia	Very frequent (80-99%)
HP:0002013	Vomiting	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0002352	Leukoencephalopathy	Very frequent (80-99%)
HP:0002415	Leukodystrophy	Very frequent (80-99%)
HP:0002421	Poor head control	Very frequent (80-99%)
HP:0002490	Increased CSF lactate	Very frequent (80-99%)
HP:0003128	Lactic acidosis	Very frequent (80-99%)
HP:0003542	Increased serum pyruvate	Very frequent (80-99%)
HP:0003737	Mitochondrial myopathy	Very frequent (80-99%)
HP:0007704	Paroxysmal involuntary eye movements	Very frequent (80-99%)
HP:0008316	Abnormal mitochondria in muscle tissue	Very frequent (80-99%)
HP:0012748	Focal T2 hyperintense brainstem lesion	Very frequent (80-99%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000618	Blindness	Occasional (5-29%)
HP:0000819	Diabetes mellitus	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0025116	Fetal distress	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex I deficiency
Mondo ID	MONDO:0100133
MeSH	C537475
Orphanet	2609
DOID	DOID:0060536
UMLS	C1838979
MedGen	374101
GARD	0003908
Is cancer (heuristic)	no

Also known as: complex 1 mitochondrial respiratory chain deficiency · isolated complex I deficiency · isolated mitochondrial respiratory chain complex I deficiency · isolated NADH-coenzyme Q reductase deficiency · isolated NADH-CoQ reductase deficiency · isolated NADH-ubiquinone reductase deficiency · mitochondrial respiratory chain complex I deficiency · NADH coenzyme Q reductase deficiency

Data availability: 202 ClinVar variants · 29 GenCC gene-disease records · 8 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › mitochondrial respiratory chain complex deficiency › mitochondrial complex I deficiency

Related subtypes (8): mitochondrial complex V (ATP synthase) deficiency, nuclear type 1, mitochondrial complex V (ATP synthase) deficiency, nuclear type 2, mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, mitochondrial complex V (ATP synthase) deficiency, nuclear type 4B, mitochondrial complex III deficiency, mitochondrial complex V (ATP synthase) deficiency, nuclear type 5, mitochondrial complex IV deficiency, nuclear-type, SDHC-related Mitochondrial Disease

Subtypes (2): mitochondrial complex I deficiency, mitochondrial type, mitochondrial complex I deficiency, nuclear type

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

202 retrieved; paginated sample, class counts are floors:

55 uncertain significance, 46 pathogenic/likely pathogenic, 34 likely pathogenic, 30 conflicting classifications of pathogenicity, 21 likely benign, 6 benign/likely benign, 4 benign, 4 pathogenic, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
7	NM_025152.2(NUBPL):c.[166G>A;815-27T>C]		Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1414680	NM_014049.5(ACAD9):c.1029+1dup	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451120	NM_014049.5(ACAD9):c.1240C>A (p.Arg414Ser)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2065147	NM_014049.5(ACAD9):c.744_747del (p.Arg249fs)	ACAD9	Pathogenic	criteria provided, multiple submitters, no conflicts
242461	NM_014049.5(ACAD9):c.1552C>T (p.Arg518Cys)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242463	NM_014049.5(ACAD9):c.1237G>A (p.Glu413Lys)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242466	NM_014049.5(ACAD9):c.796C>T (p.Arg266Trp)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242524	NM_014049.5(ACAD9):c.359del (p.Phe120fs)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30880	NM_014049.5(ACAD9):c.1249C>T (p.Arg417Cys)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30883	NM_014049.5(ACAD9):c.976G>C (p.Ala326Pro)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30884	NM_014049.5(ACAD9):c.1594C>T (p.Arg532Trp)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
848539	NM_014049.5(ACAD9):c.151-1_151del	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
95754	NM_017547.4(FOXRED1):c.612_615dup (p.Ala206fs)	FOXRED1	Pathogenic/Likely 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
1982970	NM_024120.5(NDUFAF5):c.24G>A (p.Trp8Ter)	LOC130065433	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1983600	NM_024120.5(NDUFAF5):c.23G>A (p.Trp8Ter)	LOC130065433	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2073702	NM_024120.5(NDUFAF5):c.46del (p.Ala16fs)	LOC130065433	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2121974	NM_024120.5(NDUFAF5):c.42_54del (p.Trp15fs)	LOC130065433	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2138338	NM_024120.5(NDUFAF5):c.29T>A (p.Leu10Ter)	LOC130065433	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2139992	NM_024120.5(NDUFAF5):c.44G>A (p.Trp15Ter)	LOC130065433	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676972	NM_024120.5(NDUFAF5):c.30_31del (p.Cys11fs)	LOC130065433	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2889767	NM_024120.5(NDUFAF5):c.174G>A (p.Trp58Ter)	LOC130065433	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9712	NC_012920.1(MT-ND3):m.10191T>C	MT-ND3	Pathogenic	reviewed by expert panel
790	NM_014165.4(NDUFAF4):c.194T>C (p.Leu65Pro)	NDUFAF4	Pathogenic	no assertion criteria provided
1321429	NM_024120.5(NDUFAF5):c.604C>T (p.Gln202Ter)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1909379	NM_024120.5(NDUFAF5):c.277_280del (p.Ala93fs)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2078597	NM_024120.5(NDUFAF5):c.183_190dup (p.Glu64fs)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2141476	NM_024120.5(NDUFAF5):c.204del (p.Phe68fs)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2141503	NM_024120.5(NDUFAF5):c.826C>T (p.Arg276Ter)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2154677	NM_024120.5(NDUFAF5):c.408dup (p.Ser137fs)	NDUFAF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 137 · Orphanet: 47 · 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
NDUFA1	Definitive	X-linked	mitochondrial complex I deficiency, nuclear type 12	6
NDUFB3	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 25	5
NDUFS1	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 5	6
NDUFS2	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 6	9
NDUFS7	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 3	5
NDUFS8	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 2	5
NDUFV1	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 4	6
NUBPL	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 21	4
TMEM126B	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 29	5
NDUFA11	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 14	3
NDUFA6	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 33	4
NDUFAF1	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 11	4
NDUFAF2	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 10	6
NDUFAF3	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 18	5
NDUFAF4	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 15	3
NDUFAF5	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 16	5
NDUFAF8	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 34	4
NDUFB10	Strong	Autosomal recessive	mitochondrial disease	3
NDUFS3	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 8	5
NDUFS4	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 1	7
NDUFS6	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 9	4
NDUFV2	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 7	6
TIMMDC1	Strong	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 31	4
NDUFB9	Moderate	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 24	4
MT-ND1	Supportive	Autosomal recessive	mitochondrial complex I deficiency	5
MT-ND2	Supportive	Autosomal recessive	mitochondrial complex I deficiency	3
MT-ND3	Supportive	Autosomal recessive	mitochondrial complex I deficiency	3
SLC35G2	Limited	Autosomal recessive	mitochondrial complex I deficiency

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NDUFAF5	Orphanet:2609	Isolated complex I deficiency
NDUFAF1	Orphanet:2609	Isolated complex I deficiency
NUBPL	Orphanet:2609	Isolated complex I deficiency
NDUFAF4	Orphanet:2609	Isolated complex I deficiency
FOXRED1	Orphanet:2609	Isolated complex I deficiency
NDUFAF3	Orphanet:2609	Isolated complex I deficiency
TMEM126B	Orphanet:2609	Isolated complex I deficiency
MT-ND1	Orphanet:104	Leber hereditary optic neuropathy
MT-ND1	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND1	Orphanet:2609	Isolated complex I deficiency
MT-ND1	Orphanet:550	MELAS
MT-ND2	Orphanet:104	Leber hereditary optic neuropathy
MT-ND2	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND2	Orphanet:2609	Isolated complex I deficiency
MT-ND3	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND3	Orphanet:2609	Isolated complex I deficiency
MT-ND3	Orphanet:99718	Leber plus disease
NDUFB10	Orphanet:2609	Isolated complex I deficiency
NDUFB3	Orphanet:2609	Isolated complex I deficiency
NDUFB9	Orphanet:2609	Isolated complex I deficiency
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
NDUFS4	Orphanet:2609	Isolated complex I deficiency
NDUFS6	Orphanet:2609	Isolated complex I deficiency
NDUFV1	Orphanet:2609	Isolated complex I deficiency
TIMMDC1	Orphanet:2609	Isolated complex I deficiency
NDUFA11	Orphanet:2609	Isolated complex I deficiency
NDUFAF2	Orphanet:2609	Isolated complex I deficiency
NDUFAF8	Orphanet:2609	Isolated complex I deficiency
NDUFA1	Orphanet:2609	Isolated complex I deficiency
NDUFA6	Orphanet:2609	Isolated complex I deficiency
NDUFS7	Orphanet:2609	Isolated complex I deficiency
NDUFS8	Orphanet:2609	Isolated complex I deficiency
NDUFV2	Orphanet:139447	Progressive cavitating leukoencephalopathy
NDUFV2	Orphanet:2609	Isolated complex I deficiency
NDUFA13	Orphanet:146	Differentiated thyroid carcinoma
NDUFB11	Orphanet:2556	Microphthalmia with linear skin defects syndrome
NDUFB11	Orphanet:2609	Isolated complex I deficiency
ACAD9	Orphanet:99901	Acyl-CoA dehydrogenase 9 deficiency
NDUFAF6	Orphanet:3337	Primary Fanconi renotubular syndrome
MT-ND4	Orphanet:104	Leber hereditary optic neuropathy
MT-ND4	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND4	Orphanet:550	MELAS
MT-ND4	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
MT-ND4	Orphanet:99718	Leber plus disease

Cohort genes → proteins

38 cohort genes, 37 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	38

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NDUFAF5	HGNC:15899	ENSG00000101247	Q5TEU4	Arginine-hydroxylase NDUFAF5, mitochondrial	gencc,clinvar
NDUFAF1	HGNC:18828	ENSG00000137806	Q9Y375	Complex I intermediate-associated protein 30, mitochondrial	gencc,clinvar
NUBPL	HGNC:20278	ENSG00000151413	Q8TB37	Iron-sulfur cluster transfer protein NUBPL	gencc,clinvar
NDUFAF4	HGNC:21034	ENSG00000123545	Q9P032	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 4	gencc,clinvar
FOXRED1	HGNC:26927	ENSG00000110074	Q96CU9	FAD-dependent oxidoreductase domain-containing protein 1	gencc,clinvar
NDUFAF3	HGNC:29918	ENSG00000178057	Q9BU61	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3	gencc,clinvar
TMEM126B	HGNC:30883	ENSG00000171204	Q8IUX1	Complex I assembly factor TMEM126B, mitochondrial	gencc,clinvar
MT-ND1	HGNC:7455	ENSG00000198888	P03886	NADH-ubiquinone oxidoreductase chain 1	gencc,clinvar
MT-ND2	HGNC:7456	ENSG00000198763	P03891	NADH-ubiquinone oxidoreductase chain 2	gencc,clinvar
MT-ND3	HGNC:7458	ENSG00000198840	P03897	NADH-ubiquinone oxidoreductase chain 3	gencc,clinvar
NDUFB10	HGNC:7696	ENSG00000140990	O96000	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10	gencc,clinvar
NDUFB3	HGNC:7698	ENSG00000119013	O43676	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3	gencc,clinvar
NDUFB9	HGNC:7704	ENSG00000147684	Q9Y6M9	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9	gencc,clinvar
NDUFS1	HGNC:7707	ENSG00000023228	P28331	NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial	gencc,clinvar
NDUFS2	HGNC:7708	ENSG00000158864	O75306	NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial	gencc,clinvar
NDUFS3	HGNC:7710	ENSG00000213619	O75489	NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial	gencc,clinvar
NDUFS4	HGNC:7711	ENSG00000164258	O43181	NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial	gencc,clinvar
NDUFS6	HGNC:7713	ENSG00000145494	O75380	NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial	gencc,clinvar
NDUFV1	HGNC:7716	ENSG00000167792	P49821	NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial	gencc,clinvar
TIMMDC1	HGNC:1321	ENSG00000113845	Q9NPL8	Complex I assembly factor TIMMDC1, mitochondrial	gencc
NDUFA11	HGNC:20371	ENSG00000174886	Q86Y39	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11	gencc
NDUFAF2	HGNC:28086	ENSG00000164182	Q8N183	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 2	gencc
SLC35G2	HGNC:28480	ENSG00000168917	Q8TBE7	Solute carrier family 35 member G2	gencc
NDUFAF8	HGNC:33551	ENSG00000224877	A1L188	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 8	gencc
NDUFA1	HGNC:7683	ENSG00000125356	O15239	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1	gencc
NDUFA6	HGNC:7690	ENSG00000184983	P56556	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6	gencc
NDUFS7	HGNC:7714	ENSG00000115286	O75251	NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial	gencc
NDUFS8	HGNC:7715	ENSG00000110717	O00217	NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial	gencc
NDUFV2	HGNC:7717	ENSG00000178127	P19404	NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial	gencc
SLC25A10	HGNC:10980	ENSG00000183048	Q9UBX3	Mitochondrial dicarboxylate carrier	clinvar
MRPL36	HGNC:14490	ENSG00000171421	Q9P0J6	Large ribosomal subunit protein bL36m	clinvar
NDUFA13	HGNC:17194	ENSG00000186010	Q9P0J0	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13	clinvar
NDUFB11	HGNC:20372	ENSG00000147123	Q9NX14	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial	clinvar
ACAD9	HGNC:21497	ENSG00000177646	Q9H845	Complex I assembly factor ACAD9, mitochondrial	clinvar
NDUFAF6	HGNC:28625	ENSG00000156170	Q330K2	NADH dehydrogenase (ubiquinone) complex I, assembly factor 6	clinvar
NDUFAF7	HGNC:28816	ENSG00000003509	Q7L592	Protein arginine methyltransferase NDUFAF7, mitochondrial	clinvar
C1QTNF3-AMACR	HGNC:49198	ENSG00000273294		C1QTNF3-AMACR readthrough (NMD candidate)	clinvar
MT-ND4	HGNC:7459	ENSG00000198886	C0HME5	Mitochondrial alternative ND4 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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).
NDUFAF4	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 4	Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I).
FOXRED1	FAD-dependent oxidoreductase domain-containing protein 1	Required for the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I).
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.
MT-ND1	NADH-ubiquinone oxidoreductase chain 1	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.
MT-ND2	NADH-ubiquinone oxidoreductase chain 2	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.
MT-ND3	NADH-ubiquinone oxidoreductase chain 3	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.
NDUFB10	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10	Accessory subunit that is involved in the functional assembly of the mitochondrial respiratory chain complex I.
NDUFB3	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
NDUFB9	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed to be not 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.
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.
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.
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.
TIMMDC1	Complex I assembly factor TIMMDC1, mitochondrial	Chaperone protein involved in the assembly of the mitochondrial NADH:ubiquinone oxidoreductase complex (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.
NDUFAF2	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 2	Acts as a molecular chaperone for mitochondrial complex I assembly.
NDUFAF8	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 8	Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1).
NDUFA1	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
NDUFA6	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed to be not 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.
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.
SLC25A10	Mitochondrial dicarboxylate carrier	Catalyzes the electroneutral exchange or flux of physiologically important metabolites such as dicarboxylates (malonate, malate, succinate), inorganic sulfur-containing anions, and phosphate, across the mitochondrial inner membrane.
NDUFA13	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13	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.
ACAD9	Complex I assembly factor ACAD9, mitochondrial	Together with NDUFAF1 and ECSIT, forms part of the mitochondrial complex I (MCIA),which is required for the biogenesis of respiratory Complex I (CI) and is therefore crucial for the activation of the oxidative phosphorylation system.
NDUFAF6	NADH dehydrogenase (ubiquinone) complex I, assembly factor 6	Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I) at early stages.
NDUFAF7	Protein arginine methyltransferase NDUFAF7, mitochondrial	Arginine methyltransferase involved in the assembly or stability of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I).
MT-ND4	Mitochondrial alternative ND4 protein	Regulates mitochondrial respiration by decreasing oxygen consumption.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 36 · Druggable fraction: 0.03

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	36	1.7×	3e-07
Transporter	1	2.0×	0.583
Transcription factor	1	0.2×	0.993

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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
NDUFAF4	Other/Unknown	no		NDUFAF4
FOXRED1	Other/Unknown	no		FAD-dep_OxRdtase, FAD/NAD-bd_sf
NDUFAF3	Other/Unknown	no		NDUFAF3/AAMDC, NDUF3, MTH938-like_sf
TMEM126B	Other/Unknown	no		TMEM126
MT-ND1	Other/Unknown	no		NADH_UbQ_OxRdtase_su1/FPO, NADH_UbQ_OxRdtase_su1_CS
MT-ND2	Other/Unknown	no		ND/Mrp_TM, NADH_UbQ_OxRdtase_chain2, NADH_DH_su2_C
MT-ND3	Other/Unknown	no		NADH_UbQ/plastoQ_OxRdtase_su3, NDAH_ubi_oxred_su3_sf
NDUFB10	Other/Unknown	no		NADH_UbQ_OxRdtase_su10, NDUFB10
NDUFB3	Other/Unknown	no		NDUFB3
NDUFB9	Other/Unknown	no		Complex1_LYR_dom, NDUFB9, Complex1_LYR_NDUFB9_LYRM3
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
NDUFS4	Other/Unknown	no		NADH_UbQ_FeS_4_mit-like, NDUFS4-like_sf
NDUFS6	Transcription factor	no		NDUFS6, Znf_CHCC
NDUFV1	Other/Unknown	no		NADH-UbQ_OxRdtase_51kDa_CS, NADH-UbQ_OxRdtase_suF, Nuo51_FMN-bd
TIMMDC1	Other/Unknown	no		TIMMDC1
NDUFA11	Other/Unknown	no		NDUFA11
NDUFAF2	Other/Unknown	no		NDUFA12, ComplexI_NDUFA12
SLC35G2	Other/Unknown	no		EamA_dom, EmrE-like
NDUFAF8	Other/Unknown	no		NDUFAF8
NDUFA1	Other/Unknown	no		NADH_Ub_cplx-1_asu_su-1
NDUFA6	Other/Unknown	no		NADH_Ub_cplx-1_asu_su-6, Complex1_LYR_NDUFA6_LYRM6
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
NDUFV2	Other/Unknown	no		NuoE-like, Thioredoxin-like_sf, NuoE_N
SLC25A10	Transporter	yes		MCP, MCP_transmembrane, MCP_dom_sf
MRPL36	Other/Unknown	no		Ribosomal_bL36, Ribosomal_bL36_sp, Mitoribosomal_bL36m
NDUFA13	Other/Unknown	no		GRIM-19
NDUFB11	Other/Unknown	no		NADH_UbQ_OxRdtase_ESSS_su
ACAD9	Other/Unknown	no		Acyl-CoA_DH_CS, AcylCoA_DH/ox_M, AcylCo_DH/oxidase_C
NDUFAF6	Other/Unknown	no		Squ/phyt_synthse, Isoprenoid_synthase_dom_sf
NDUFAF7	Other/Unknown	no		NDUFAF7, SAM-dependent_MTases_sf, NDUFAF7_sf
C1QTNF3-AMACR	Other/Unknown	no
MT-ND4	Other/Unknown	no		NADH4_N, ND/Mrp_TM, NADH_UbQ_OxRdtase

Expression context

Cohort genes with no expression data: 0.

37 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)	38
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	14
gastrocnemius	7
left ventricle myocardium	7
hindlimb stylopod muscle	6
right atrium auricular region	5
heart left ventricle	5
cardiac muscle of right atrium	4
calcaneal tendon	3
adipose tissue	3
right uterine tube	3
right adrenal gland	2
adrenal tissue	2
right hemisphere of cerebellum	2
left testis	2
right testis	2
granulocyte	2
myocardium	2
mucosa of transverse colon	2
putamen	2
pancreatic ductal cell	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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
NDUFAF4	286	ubiquitous	marker	pons, lateral nuclear group of thalamus, heart right ventricle
FOXRED1	232	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
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
MT-ND1	134	ubiquitous	marker	adipose tissue, gastrocnemius, frontal cortex
MT-ND2	134	broad	marker	adipose tissue, right uterine tube, left uterine tube
MT-ND3	134	ubiquitous	marker	granulocyte, adipose tissue, left lobe of thyroid gland
NDUFB10	255	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
NDUFB3	297	ubiquitous	marker	heart left ventricle, right atrium auricular region, apex of heart
NDUFB9	255	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, kidney epithelium
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
NDUFS4	294	ubiquitous	marker	calcaneal tendon, skeletal muscle tissue of rectus abdominis, hindlimb stylopod muscle
NDUFS6	295	ubiquitous	marker	tendon of biceps brachii, apex of heart, right atrium auricular region
NDUFV1	292	ubiquitous	marker	apex of heart, right hemisphere of cerebellum, metanephros cortex
TIMMDC1	259	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
NDUFA11	260	ubiquitous	marker	pancreatic ductal cell, cardiac muscle of right atrium, left ventricle myocardium
NDUFAF2	139	ubiquitous	marker	calcaneal tendon, lower esophagus muscularis layer, gastrocnemius
SLC35G2	222	ubiquitous	marker	sperm, cartilage tissue, secondary oocyte
NDUFAF8	253	ubiquitous	marker	medial globus pallidus, putamen, globus pallidus
NDUFA1	294	ubiquitous	marker	left ventricle myocardium, cardiac ventricle, heart left ventricle
NDUFA6	134	ubiquitous	marker	hindlimb stylopod muscle, heart left ventricle, 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
NDUFV2	137	ubiquitous	marker	apex of heart, gastrocnemius, hindlimb stylopod muscle
SLC25A10	133	ubiquitous	marker	right lobe of liver, mucosa of transverse colon, liver

Protein interactions among cohort

Intra-cohort edges: 272.

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
ACAD9	3,600
MT-ND1	3,537
NDUFA13	3,268

Intra-cohort edges

A	B	Sources
ACAD9	FOXRED1	intact, string_interaction
ACAD9	MT-ND2	string_interaction
ACAD9	NDUFA1	string_interaction
ACAD9	NDUFA13	biogrid_interaction, intact
ACAD9	NDUFAF1	biogrid_interaction, intact, string_interaction
ACAD9	NDUFAF3	biogrid_interaction
ACAD9	NDUFAF4	biogrid_interaction, intact, string_interaction
ACAD9	NDUFAF5	intact, string_interaction
ACAD9	NDUFAF6	string_interaction
ACAD9	NDUFAF7	string_interaction
ACAD9	NDUFS2	biogrid_interaction
ACAD9	NDUFS3	biogrid_interaction, intact
ACAD9	NDUFS7	biogrid_interaction, intact
ACAD9	NUBPL	string_interaction
ACAD9	TIMMDC1	biogrid_interaction, intact, string_interaction
ACAD9	TMEM126B	biogrid_interaction, intact, string_interaction
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	NDUFAF7	biogrid_interaction, string_interaction
FOXRED1	NDUFAF8	string_interaction
FOXRED1	NDUFB10	biogrid_interaction
FOXRED1	NDUFS4	string_interaction
FOXRED1	NDUFS7	string_interaction
FOXRED1	NUBPL	string_interaction
FOXRED1	TIMMDC1	string_interaction
FOXRED1	TMEM126B	string_interaction
MT-ND1	MT-ND2	string_interaction
MT-ND1	MT-ND3	string_interaction
MT-ND1	NDUFA1	string_interaction
MT-ND1	NDUFA13	intact
MT-ND1	NDUFAF1	intact, string_interaction
MT-ND1	NDUFAF4	string_interaction
MT-ND1	NDUFB11	string_interaction
MT-ND1	NDUFS2	string_interaction
MT-ND1	NDUFS3	biogrid_interaction, intact
MT-ND1	NDUFS6	intact
MT-ND1	NDUFS7	string_interaction
MT-ND1	NDUFV2	intact
MT-ND1	TIMMDC1	intact
MT-ND2	MT-ND3	string_interaction
MT-ND2	NDUFA11	intact
MT-ND2	NDUFA6	intact
MT-ND2	NDUFB11	intact
MT-ND2	NDUFB3	intact
MT-ND2	NDUFS1	string_interaction
MT-ND2	NDUFS3	intact

Structural data

PDB: 23 · AlphaFold-only: 14 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPL36	Q9P0J6	73
NDUFS2	O75306	8
NDUFA13	Q9P0J0	8
MT-ND2	P03891	7
NDUFB10	O96000	7
NDUFB3	O43676	7
NDUFB9	Q9Y6M9	7
NDUFS1	P28331	7
NDUFS3	O75489	7
NDUFS4	O43181	7
NDUFS6	O75380	7
NDUFV1	P49821	7
NDUFA11	Q86Y39	7
NDUFA1	O15239	7
NDUFA6	P56556	7
NDUFS7	O75251	7
NDUFS8	O00217	7
NDUFV2	P19404	7
NDUFB11	Q9NX14	7
MT-ND4	C0HME5	7
MT-ND1	P03886	5
MT-ND3	P03897	5
ACAD9	Q9H845	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NDUFAF8	A1L188	91.12
FOXRED1	Q96CU9	90.12
NDUFAF6	Q330K2	87.70
NDUFAF7	Q7L592	85.54
NDUFAF5	Q5TEU4	85.43
NUBPL	Q8TB37	85.40
NDUFAF4	Q9P032	83.37
TMEM126B	Q8IUX1	82.06
NDUFAF3	Q9BU61	79.02
NDUFAF2	Q8N183	78.98
SLC35G2	Q8TBE7	77.60
SLC25A10	Q9UBX3	77.53
NDUFAF1	Q9Y375	73.37
TIMMDC1	Q9NPL8	72.08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 38 evidence-associated genes (36 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 36 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	34	156.3×	2e-76	NDUFAF5, NDUFAF1, NUBPL, NDUFAF4, FOXRED1, NDUFAF3, TMEM126B, MT-ND1 (+26 more)
Respiratory electron transport	31	82.0×	2e-57	NDUFAF5, NDUFAF4, NDUFAF3, TMEM126B, MT-ND1, MT-ND2, MT-ND3, NDUFB10 (+23 more)
Aerobic respiration and respiratory electron transport	27	66.4×	8e-46	NDUFAF5, NDUFAF4, NDUFAF3, TMEM126B, NDUFB10, NDUFB3, NDUFB9, NDUFS1 (+19 more)
Metabolism	27	8.7×	3e-21	NDUFAF5, NDUFAF4, NDUFAF3, TMEM126B, NDUFB10, NDUFB3, NDUFB9, NDUFS1 (+19 more)
Mitochondrial protein degradation	6	19.0×	2e-06	MT-ND1, MT-ND2, NDUFS1, NDUFS3, NDUFV1, NDUFA13
Mitochondrial translation termination	5	15.2×	5e-05	MT-ND1, MT-ND2, MT-ND3, MRPL36, MT-ND4
Sulfide oxidation to sulfate	1	52.9×	0.051	SLC25A10
Organic anion transport by SLC5/17/25 transporters	1	39.6×	0.059	SLC25A10
Metabolism of proteins	5	1.7×	0.341	NDUFS1, NDUFS3, NDUFV1, MRPL36, NDUFA13
RHOG GTPase cycle	1	4.1×	0.347	NDUFS3
Mitochondrial translation	1	3.8×	0.347	MRPL36
Mitochondrial translation initiation	1	3.5×	0.347	MRPL36
Mitochondrial translation elongation	1	3.5×	0.347	MRPL36
Mitochondrial ribosome-associated quality control	1	3.4×	0.347	MRPL36
Translation	1	1.7×	0.539	MRPL36
RHO GTPase cycle	1	1.7×	0.539	NDUFS3
Signaling by Rho GTPases	1	0.9×	0.702	NDUFS3
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	0.9×	0.702	NDUFS3
Signal Transduction	1	0.3×	0.976	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 36 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	25	285.4×	2e-59	NDUFAF5, NDUFAF1, NUBPL, NDUFAF4, FOXRED1, NDUFAF3, TMEM126B, MT-ND1 (+17 more)
mitochondrial electron transport, NADH to ubiquinone	20	199.2×	2e-42	NDUFAF1, MT-ND1, MT-ND2, MT-ND3, NDUFB10, NDUFB3, NDUFB9, NDUFS1 (+12 more)
proton motive force-driven mitochondrial ATP synthesis	21	153.6×	5e-42	MT-ND1, MT-ND2, MT-ND3, NDUFB10, NDUFB3, NDUFB9, NDUFS1, NDUFS2 (+13 more)
aerobic respiration	21	144.6×	2e-41	MT-ND1, MT-ND2, MT-ND3, NDUFB10, NDUFB3, NDUFB9, NDUFS1, NDUFS2 (+13 more)
reactive oxygen species metabolic process	4	52.0×	1e-05	MT-ND2, NDUFS3, NDUFS4, NDUFS6
electron transport coupled proton transport	2	234.1×	3e-04	MT-ND4, NDUFS7
mitochondrial ATP synthesis coupled electron transport	2	104.0×	0.002	NDUFS2, NDUFV1
thiosulfate transport	1	468.1×	0.016	SLC25A10
peptidyl-arginine methylation, to symmetrical-dimethyl arginine	1	468.1×	0.016	NDUFAF7
malate transmembrane transport	1	468.1×	0.016	SLC25A10
oxaloacetate transport	1	234.1×	0.025	SLC25A10
mesenchymal stem cell differentiation	1	234.1×	0.025	NDUFS6
mesenchymal stem cell proliferation	1	234.1×	0.025	NDUFS6
dicarboxylic acid transport	1	156.0×	0.030	SLC25A10
obsolete sulfide oxidation, using sulfide:quinone oxidoreductase	1	156.0×	0.030	SLC25A10
response to hypoxia	3	8.0×	0.030	MT-ND1, MT-ND2, MT-ND4
glyceraldehyde-3-phosphate biosynthetic process	1	117.0×	0.034	SLC25A10
succinate transmembrane transport	1	117.0×	0.034	SLC25A10
cellular response to oxygen levels	1	117.0×	0.034	NDUFS2
gliogenesis	1	78.0×	0.046	NDUFS2
medium-chain fatty acid metabolic process	1	78.0×	0.046	ACAD9
reproductive system development	1	66.9×	0.051	NDUFS6
response to light intensity	1	58.5×	0.055	MT-ND3
stem cell division	1	52.0×	0.060	NDUFS6
response to hydroperoxide	1	46.8×	0.061	MT-ND1
negative regulation of insulin secretion involved in cellular response to glucose stimulus	1	46.8×	0.061	NDUFAF2
circulatory system development	1	39.0×	0.070	NDUFS6
protein insertion into mitochondrial inner membrane	1	36.0×	0.073	NDUFA13
phosphate ion transmembrane transport	1	33.4×	0.074	SLC25A10
sulfate transmembrane transport	1	33.4×	0.074	SLC25A10

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 37

Druggability breadth: 26 of 38 evidence-associated genes (68%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NDUFA13	1	3
NDUFAF5	0	0
NDUFAF1	0	0
NUBPL	0	0
NDUFAF4	0	0
FOXRED1	0	0
NDUFAF3	0	0
TMEM126B	0	0
MT-ND1	0	0
MT-ND2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ALISERTIB	3	NDUFA13

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
NDUFA13	6	Binding:6
NDUFAF4	5	Binding:5
MT-ND1	5	Binding:5
NDUFB10	5	Binding:5
NDUFB9	5	Binding:5
NDUFS1	5	Binding:5
NDUFS3	5	Binding:5
NDUFS6	5	Binding:5
NDUFV1	5	Binding:5
NDUFAF2	5	Binding:5
NDUFS7	5	Binding:5
NDUFV2	5	Binding:5
NDUFAF1	4	Binding:4
NDUFAF3	4	Binding:4
MT-ND2	4	Binding:4
MT-ND3	4	Binding:4
NDUFB3	4	Binding:4
NDUFS4	4	Binding:4
NDUFA11	4	Binding:4
NDUFA1	4	Binding:4
NDUFA6	4	Binding:4
NDUFS8	4	Binding:4
NDUFB11	4	Binding:4
ACAD9	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 37; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
ALISERTIB	3	NDUFA13

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	1	NDUFA13
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	SLC25A10
E	Difficult family or no structure, no drug	36	NDUFAF5, NDUFAF1, NUBPL, NDUFAF4, FOXRED1, NDUFAF3, TMEM126B, MT-ND1, MT-ND2, MT-ND3 (+26 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NDUFAF5	0	—
NDUFAF1	4	—
NUBPL	0	—
NDUFAF4	5	—
FOXRED1	0	—
NDUFAF3	4	—
TMEM126B	0	—
MT-ND1	5	—
MT-ND2	4	—
MT-ND3	4	—
NDUFB10	5	—
NDUFB3	4	—
NDUFB9	5	—
NDUFS1	5	—
NDUFS2	11	—
NDUFS3	5	—
NDUFS4	4	—
NDUFS6	5	—
NDUFV1	5	—
TIMMDC1	0	—
NDUFA11	4	—
NDUFAF2	5	—
SLC35G2	0	—
NDUFAF8	0	—
NDUFA1	4	—
NDUFA6	4	—
NDUFS7	5	—
NDUFS8	4	—
NDUFV2	5	—
SLC25A10	0	—

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