Mitochondrial disease

Summary

Mitochondrial disease (MONDO:0044970) is a disease (an umbrella term covering 12 Mondo subtypes) caused by variants in MICOS13, SLC25A4, DAP3, and 6 other genes, with 75 cohort genes and 103 clinical trials. The dominant Reactome pathway is Respiratory electron transport (23 cohort genes). Top therapeutic interventions include dextromethorphan, cysteamine bitartrate, and esflurbiprofen.

At a glance

• Causal genes: MICOS13 (GenCC Definitive), SLC25A4 (GenCC Definitive), DAP3 (GenCC Strong), DGUOK (GenCC Strong) (+5 more)
• Umbrella term: 12 Mondo subtypes
• Cohort genes: 75
• ClinVar variants: 653
• Clinical trials: 103

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial disease
Mondo ID	MONDO:0044970
UMLS	C0751651
MedGen	155901
GARD	0027984
Is cancer (heuristic)	no

Data availability: 653 ClinVar variants · 332 ClinGen variant curations · 24 GenCC gene-disease records.

Disease family

An umbrella term covering 12 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › mitochondrial disease

Related subtypes (11): psychiatric disorder, metabolic disease, premature aging syndrome, disorder of development or morphogenesis, inflammatory disease, disorder of glycosylation, ulcer disease, sleep disorder, perinatal disease, obstetric disorder, disease by molecular mechanism

Subtypes (12): inborn mitochondrial metabolism disorder, hereditary myopathy with lactic acidosis due to ISCU deficiency, Bjornstad syndrome, X-linked sideroblastic anemia with ataxia, ethylmalonic encephalopathy, GRACILE syndrome, mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency, autosomal dominant optic atrophy plus syndrome, maternally-inherited cardiomyopathy and hearing loss, pure mitochondrial myopathy, FDXR-related optic atrophy mitochondrial dysfunction syndrome, ACO2-related optic atrophy with or without extraocular features

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:

244 uncertain significance, 116 likely pathogenic, 106 pathogenic, 51 conflicting classifications of pathogenicity, 40 pathogenic/likely pathogenic, 30 benign, 8 likely benign, 3 benign/likely benign, 1 pathogenic; drug response, 1 likely pathogenic; drug response

ClinVar	Variant (HGVS)	Gene	Classification	Review
30940	NM_020745.4(AARS2):c.1774C>T (p.Arg592Trp)	AARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
489386	NM_001687.5(ATP5F1D):c.317T>G (p.Val106Gly)	ATP5F1D	Pathogenic	no assertion criteria provided
441242	NM_001212.4(C1QBP):c.612C>G (p.Phe204Leu)	C1QBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225002	NM_020247.5(COQ8A):c.1015G>A (p.Ala339Thr)	COQ8A	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
440787	NM_032380.5(GFM2):c.636del (p.Glu213fs)	GFM2	Pathogenic	no assertion criteria provided
440788	NM_032380.5(GFM2):c.275A>C (p.Tyr92Ser)	GFM2	Pathogenic	no assertion criteria provided
383938	NM_198076.6(COX20):c.41A>G (p.Lys14Arg)	LOC129932912	Pathogenic	criteria provided, multiple submitters, no conflicts
132103	NM_015713.5(RRM2B):c.48G>A (p.Glu16=)	LOC130000896	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280013	NM_004614.5(TK2):c.103C>T (p.Gln35Ter)	LOC130059156	Pathogenic	criteria provided, multiple submitters, no conflicts
691643	NM_001086521.2(NDUFAF8):c.1A>G (p.Met1Val)	LOC130061928	Pathogenic	criteria provided, single submitter
374878	NM_016011.5(MECR):c.695G>A (p.Gly232Glu)	MECR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449055	NM_016011.5(MECR):c.830+2dup	MECR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16160	NM_002437.5(MPV17):c.149G>A (p.Arg50Gln)	MPV17	Pathogenic	criteria provided, multiple submitters, no conflicts
1676674	NM_017446.4(MRPL39):c.589-924G>A	MRPL39	Pathogenic	criteria provided, single submitter
2691723	NM_004927.4(MRPL49):c.262C>T (p.Arg88Cys)	MRPL49	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2691726	NM_004927.4(MRPL49):c.125_126del (p.Val42fs)	MRPL49	Pathogenic	criteria provided, single submitter
9641	NC_012920.1(MT-ATP6):m.8993T>G	MT-ATP6	Pathogenic	reviewed by expert panel
9642	NC_012920.1(MT-ATP6):m.8993T>C	MT-ATP6	Pathogenic	reviewed by expert panel
9644	NC_012920.1(MT-ATP6):m.9176T>C	MT-ATP6	Pathogenic	reviewed by expert panel
9647	NC_012920.1(MT-ATP6):m.9185T>C	MT-ATP6	Pathogenic	reviewed by expert panel
430676	NC_012920.1(MT-TS2):m.7129_13991del	MT-ATP8	Pathogenic	no assertion criteria provided
9563	NC_012920.1(MT-TS1):m.7445A>G	MT-CO1	Pathogenic	reviewed by expert panel
430677	NC_012920.1(MT-TR):m.7731_11256del	MT-CO2	Pathogenic	no assertion criteria provided
9662	NC_012920.1(MT-CO2):m.7896G>A	MT-CO2	Pathogenic	reviewed by expert panel
430674	NC_012920.1(MT-TS1):m.6005_11222del	MT-CO3	Pathogenic	no assertion criteria provided
9628	NC_012920.1(MT-RNR1):m.1555A>G	MT-ND1	Pathogenic; drug response	reviewed by expert panel
4528936	NC_012920.1:m.8478_13589del	MT-ND3	Pathogenic	criteria provided, single submitter
430685	NC_012920.1(MT-TS2):m.11263_15374del	MT-ND4	Pathogenic	no assertion criteria provided
430682	NC_012920.1(MT-TS2):m.8815_13722del	MT-ND4L	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 86 · Orphanet: 112 · 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
DGUOK	Definitive	Autosomal recessive	mitochondrial DNA depletion syndrome 3 (hepatocerebral type)	6
MICOS13	Definitive	Autosomal recessive	mitochondrial disease	2
SLC25A4	Definitive	Autosomal recessive	mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive	14
ATP5F1A	Strong	Autosomal dominant	mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A	7
DAP3	Strong	Autosomal recessive	mitochondrial disease
DLGAP3	Strong	Autosomal recessive	mitochondrial disease
GUK1	Strong	Autosomal recessive	mitochondrial DNA depletion syndrome	2
LYRM7	Strong	Autosomal recessive	mitochondrial complex III deficiency nuclear type 8	3
MARS2	Strong	Autosomal recessive	mitochondrial disease	7
MRPL49	Strong	Autosomal recessive	mitochondrial disease
NDUFB10	Strong	Autosomal recessive	mitochondrial disease	3
PDE12	Strong	Autosomal recessive	mitochondrial disease	2
APOO	Moderate	X-linked	mitochondrial disease	2
GARS1	Moderate	Autosomal recessive	mitochondrial disease	9
MRPL50	Moderate	Autosomal recessive	mitochondrial disease
NARS2	Moderate	Autosomal recessive	mitochondrial disease	9
TIMM22	Moderate	Autosomal recessive	mitochondrial disease	3
TMEM65	Moderate	Autosomal recessive	mitochondrial disease
TOMM70	Moderate	Autosomal recessive	mitochondrial disease	4
MT-ATP8	Supportive	Autosomal recessive	mitochondrial proton-transporting ATP synthase complex deficiency	3
MT-TL1	Limited	Mitochondrial	mitochondrial disease	3
PNPLA4	Limited	X-linked	mitochondrial disease
PYROXD2	Limited	Autosomal recessive	mitochondrial disease

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC25A4	Orphanet:1369	Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome
SLC25A4	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
NARS2	Orphanet:444458	Combined oxidative phosphorylation defect type 24
NARS2	Orphanet:79134	DEND syndrome
NARS2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
DGUOK	Orphanet:279934	Mitochondrial DNA depletion syndrome, hepatocerebral form due to DGUOK deficiency
DGUOK	Orphanet:329314	Adult-onset multiple mitochondrial DNA deletion syndrome due to DGUOK deficiency
MT-ATP8	Orphanet:254913	Isolated ATP synthase deficiency
MT-ATP8	Orphanet:397750	Periodic paralysis with later-onset distal motor neuropathy
MT-ATP8	Orphanet:480	Kearns-Sayre syndrome
MT-TL1	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-TL1	Orphanet:324525	Hypertrophic cardiomyopathy with kidney anomalies due to mitochondrial DNA mutation
MT-TL1	Orphanet:480	Kearns-Sayre syndrome
MT-TL1	Orphanet:550	MELAS
MT-TL1	Orphanet:551	MERRF
MT-TL1	Orphanet:663	Mitochondrial DNA-related progressive external ophthalmoplegia
ATP5F1A	Orphanet:254913	Isolated ATP synthase deficiency
MARS2	Orphanet:314603	Autosomal recessive spastic ataxia with leukoencephalopathy
MARS2	Orphanet:447954	Combined oxidative phosphorylation defect type 25
LYRM7	Orphanet:1460	Isolated complex III deficiency
MICOS13	Orphanet:67047	3-methylglutaconic aciduria type 3
GARS1	Orphanet:139536	Distal hereditary motor neuropathy type 5
GARS1	Orphanet:99938	Autosomal dominant Charcot-Marie-Tooth disease type 2D
NDUFB10	Orphanet:2609	Isolated complex I deficiency
SPG7	Orphanet:35689	Primary lateral sclerosis
SPG7	Orphanet:99013	Spastic paraplegia type 7
SURF1	Orphanet:391351	SURF1-related Charcot-Marie-Tooth disease type 4
TWNK	Orphanet:1186	Infantile-onset spinocerebellar ataxia
TWNK	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
TWNK	Orphanet:363534	Mitochondrial DNA depletion syndrome, hepatocerebrorenal form
TWNK	Orphanet:642945	Perrault syndrome type 1
TWNK	Orphanet:642976	Perrault syndrome type 2
TWNK	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
ACO2	Orphanet:313850	Infantile cerebellar-retinal degeneration
ACO2	Orphanet:98676	Autosomal recessive isolated optic atrophy
TK2	Orphanet:254875	Mitochondrial DNA depletion syndrome, myopathic form
TK2	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia
MED12	Orphanet:1415	Hardikar syndrome
MED12	Orphanet:293707	Blepharophimosis-intellectual disability syndrome, MKB type
MED12	Orphanet:776	Lujan-Fryns syndrome
MED12	Orphanet:777	X-linked non-syndromic intellectual disability
MED12	Orphanet:93932	FG syndrome type 1
TOP3A	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia
TOP3A	Orphanet:508512	Intrauterine growth restriction-congenital multiple café-au-lait macules-increased sister chromatid exchange syndrome
TUFM	Orphanet:254925	Combined oxidative phosphorylation defect type 4
UQCRC2	Orphanet:1460	Isolated complex III deficiency
WARS2	Orphanet:238455	Infantile dystonia-parkinsonism
WARS2	Orphanet:572798	WARS2-related combined oxidative phosphorylation defect
FBXL4	Orphanet:369897	Mitochondrial DNA depletion syndrome, encephalomyopathic form with variable craniofacial anomalies
MRPS22	Orphanet:137908	Hypotonia with lactic acidemia and hyperammonemia

Cohort genes → proteins

75 cohort genes, 74 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	75

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC25A4	HGNC:10990	ENSG00000151729	P12235	ADP/ATP translocase 1	gencc,clinvar
MRPL49	HGNC:1176	ENSG00000149792	Q13405	Large ribosomal subunit protein mL49	gencc,clinvar
NARS2	HGNC:26274	ENSG00000137513	Q96I59	Asparaginyl-tRNA synthetase	gencc,clinvar
DGUOK	HGNC:2858	ENSG00000114956	Q16854	Deoxyguanosine kinase, mitochondrial	gencc,clinvar
MT-ATP8	HGNC:7415	ENSG00000228253	P03928	ATP synthase F(0) complex subunit 8	gencc,clinvar
MT-TL1	HGNC:7490	ENSG00000209082		mitochondrially encoded tRNA-Leu (UUA/G) 1	gencc,clinvar
ATP5F1A	HGNC:823	ENSG00000152234	P25705	ATP synthase F(1) complex subunit alpha, mitochondrial	gencc,clinvar
TOMM70	HGNC:11985	ENSG00000154174	O94826	Mitochondrial import receptor subunit TOM70	gencc
MRPL50	HGNC:16654	ENSG00000136897	Q8N5N7	Large ribosomal subunit protein mL50	gencc
TIMM22	HGNC:17317	ENSG00000177370	Q9Y584	Mitochondrial import inner membrane translocase subunit Tim22	gencc
PYROXD2	HGNC:23517	ENSG00000119943	Q8N2H3	Pyridine nucleotide-disulfide oxidoreductase domain-containing protein 2	gencc
PNPLA4	HGNC:24887	ENSG00000006757	P41247	Patatin-like phospholipase domain-containing protein 4	gencc
MARS2	HGNC:25133	ENSG00000247626	Q96GW9	Methionine–tRNA ligase, mitochondrial	gencc
TMEM65	HGNC:25203	ENSG00000164983	Q6PI78	Transmembrane protein 65	gencc
PDE12	HGNC:25386	ENSG00000174840	Q6L8Q7	2’,5’-phosphodiesterase 12	gencc
DAP3	HGNC:2673	ENSG00000132676	P51398	Small ribosomal subunit protein mS29	gencc
LYRM7	HGNC:28072	ENSG00000186687	Q5U5X0	Complex III assembly factor LYRM7	gencc
APOO	HGNC:28727	ENSG00000184831	Q9BUR5	MICOS complex subunit MIC26	gencc
DLGAP3	HGNC:30368	ENSG00000116544	O95886	Disks large-associated protein 3	gencc
MICOS13	HGNC:33702	ENSG00000174917	Q5XKP0	MICOS complex subunit MIC13	gencc
GARS1	HGNC:4162	ENSG00000106105	P41250	Glycine–tRNA ligase	gencc
GUK1	HGNC:4693	ENSG00000143774	Q16774	Guanylate kinase	gencc
NDUFB10	HGNC:7696	ENSG00000140990	O96000	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10	gencc
SPG7	HGNC:11237	ENSG00000197912	Q9UQ90	Mitochondrial inner membrane m-AAA protease component paraplegin	clinvar
SURF1	HGNC:11474	ENSG00000148290	Q15526	Surfeit locus protein 1	clinvar
TWNK	HGNC:1160	ENSG00000107815	Q96RR1	Twinkle mtDNA helicase	clinvar
ACO2	HGNC:118	ENSG00000100412	Q99798	Aconitate hydratase, mitochondrial	clinvar
TK2	HGNC:11831	ENSG00000166548	O00142	Thymidine kinase 2, mitochondrial	clinvar
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	clinvar
TOP3A	HGNC:11992	ENSG00000177302	Q13472	DNA topoisomerase 3-alpha	clinvar
TUFM	HGNC:12420	ENSG00000178952	P49411	Elongation factor Tu, mitochondrial	clinvar
C1QBP	HGNC:1243	ENSG00000108561	Q07021	Complement component 1 Q subcomponent-binding protein, mitochondrial	clinvar
UQCRC2	HGNC:12586	ENSG00000140740	P22695	Cytochrome b-c1 complex subunit 2, mitochondrial	clinvar
VARS1	HGNC:12651	ENSG00000204394	P26640	Valine–tRNA ligase	clinvar
WARS2	HGNC:12730	ENSG00000116874	Q9UGM6	Tryptophan–tRNA ligase, mitochondrial	clinvar
FBXL4	HGNC:13601	ENSG00000112234	Q9UKA2	F-box/LRR-repeat protein 4	clinvar
MRPL39	HGNC:14027	ENSG00000154719	Q9NYK5	Large ribosomal subunit protein mL39	clinvar
MRPS22	HGNC:14508	ENSG00000175110	P82650	Small ribosomal subunit protein mS22	clinvar
PUS1	HGNC:15508	ENSG00000177192	Q9Y606	Pseudouridylate synthase 1 homolog	clinvar
COQ8A	HGNC:16812	ENSG00000163050	Q8NI60	Atypical kinase COQ8A, mitochondrial	clinvar
RRM2B	HGNC:17296	ENSG00000048392	Q7LG56	Ribonucleoside-diphosphate reductase subunit M2 B	clinvar
COQ8B	HGNC:19041	ENSG00000123815	Q96D53	Atypical kinase COQ8B, mitochondrial	clinvar
MECR	HGNC:19691	ENSG00000116353	Q9BV79	Enoyl-[acyl-carrier-protein] reductase, mitochondrial	clinvar
TRIT1	HGNC:20286	ENSG00000043514	Q9H3H1	tRNA dimethylallyltransferase	clinvar
AARS2	HGNC:21022	ENSG00000124608	Q5JTZ9	Alanine–tRNA ligase, mitochondrial	clinvar
RMND1	HGNC:21176	ENSG00000155906	Q9NWS8	Required for meiotic nuclear division protein 1 homolog	clinvar
PDHX	HGNC:21350	ENSG00000110435	O00330	Pyruvate dehydrogenase protein X component, mitochondrial	clinvar
RARS2	HGNC:21406	ENSG00000146282	Q5T160	Probable arginine–tRNA ligase, mitochondrial	clinvar
VARS2	HGNC:21642	ENSG00000137411	Q5ST30	Valine–tRNA ligase, mitochondrial	clinvar
AGK	HGNC:21869	ENSG00000006530	Q53H12	Acylglycerol kinase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC25A4	ADP/ATP translocase 1	ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell.
NARS2	Asparaginyl-tRNA synthetase	Mitochondrial aminoacyl-tRNA synthetase that catalyzes the specific attachment of the asparagine amino acid (aa) to the homologous transfer RNA (tRNA), further participating in protein synthesis.
DGUOK	Deoxyguanosine kinase, mitochondrial	Phosphorylates deoxyguanosine and deoxyadenosine in the mitochondrial matrix, with the highest efficiency for deoxyguanosine.
MT-ATP8	ATP synthase F(0) complex subunit 8	Subunit 8, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of th…
ATP5F1A	ATP synthase F(1) complex subunit alpha, mitochondrial	Subunit alpha, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes o…
TOMM70	Mitochondrial import receptor subunit TOM70	Acts as a receptor of the preprotein translocase complex of the outer mitochondrial membrane (TOM complex).
TIMM22	Mitochondrial import inner membrane translocase subunit Tim22	Essential core component of the TIM22 complex, a complex that mediates the import and insertion of multi-pass transmembrane proteins into the mitochondrial inner membrane.
PYROXD2	Pyridine nucleotide-disulfide oxidoreductase domain-containing protein 2	Probable oxidoreductase that may play a role as regulator of mitochondrial function.
PNPLA4	Patatin-like phospholipase domain-containing protein 4	Has abundant triacylglycerol lipase activity.
TMEM65	Transmembrane protein 65	Essential for maintaining proper cardiac intercalated disk (ICD) structure and function as well as cardiac conduction velocity in the heart.
PDE12	2’,5’-phosphodiesterase 12	Enzyme that cleaves 2’,5’-phosphodiester bond linking adenosines of the 5’-triphosphorylated oligoadenylates, triphosphorylated oligoadenylates referred as 2-5A modulates the 2-5A system.
DAP3	Small ribosomal subunit protein mS29	As a component of the mitochondrial small ribosomal subunit, it plays a role in the translation of mitochondrial mRNAs.
LYRM7	Complex III assembly factor LYRM7	Assembly factor required for Rieske Fe-S protein UQCRFS1 incorporation into the cytochrome b-c1 (CIII) complex.
APOO	MICOS complex subunit MIC26	Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane.
DLGAP3	Disks large-associated protein 3	May play a role in the molecular organization of synapses and neuronal cell signaling.
MICOS13	MICOS complex subunit MIC13	Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane.
GARS1	Glycine–tRNA ligase	Catalyzes the ATP-dependent ligation of glycine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (Gly-AMP).
GUK1	Guanylate kinase	Catalyzes the phosphorylation of GMP to GDP.
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.
SPG7	Mitochondrial inner membrane m-AAA protease component paraplegin	Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development.
SURF1	Surfeit locus protein 1	Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly.
TWNK	Twinkle mtDNA helicase	Mitochondrial helicase involved in mtDNA replication and repair.
ACO2	Aconitate hydratase, mitochondrial	Catalyzes the isomerization of citrate to isocitrate via cis-aconitate.
TK2	Thymidine kinase 2, mitochondrial	Phosphorylates thymidine, deoxycytidine, and deoxyuridine in the mitochondrial matrix.
MED12	Mediator of RNA polymerase II transcription subunit 12	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
TOP3A	DNA topoisomerase 3-alpha	Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex.
TUFM	Elongation factor Tu, mitochondrial	GTP hydrolase that promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis.
C1QBP	Complement component 1 Q subcomponent-binding protein, mitochondrial	Multifunctional and multicompartmental protein involved in inflammation and infection processes, ribosome biogenesis, protein synthesis in mitochondria, regulation of apoptosis, transcriptional regulation and pre-mRNA splicing.
UQCRC2	Cytochrome b-c1 complex subunit 2, mitochondrial	Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation.
VARS1	Valine–tRNA ligase	Catalyzes the attachment of valine to tRNA(Val).
WARS2	Tryptophan–tRNA ligase, mitochondrial	Catalyzes the attachment of tryptophan to tRNA(Trp) in a two-step reaction: tryptophan is first activated by ATP to form Trp-AMP and then transferred to the acceptor end of tRNA(Trp).
FBXL4	F-box/LRR-repeat protein 4	Substrate-recognition component of the mitochondria-localized SCF-FBXL4 ubiquitin E3 ligase complex that plays a role in the restriction of mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors.
PUS1	Pseudouridylate synthase 1 homolog	Pseudouridylate synthase that catalyzes pseudouridylation of tRNAs and mRNAs.
COQ8A	Atypical kinase COQ8A, mitochondrial	Atypical kinase involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration.
RRM2B	Ribonucleoside-diphosphate reductase subunit M2 B	Plays a pivotal role in cell survival by repairing damaged DNA in a p53/TP53-dependent manner.
COQ8B	Atypical kinase COQ8B, mitochondrial	Atypical kinase involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration.
MECR	Enoyl-[acyl-carrier-protein] reductase, mitochondrial	Catalyzes the NADPH-dependent reduction of trans-2-enoyl thioesters in mitochondrial fatty acid synthesis (fatty acid synthesis type II).
TRIT1	tRNA dimethylallyltransferase	Catalyzes the transfer of a dimethylallyl group onto the adenine at position 37 of both cytosolic and mitochondrial tRNAs, leading to the formation of N6-(dimethylallyl)adenosine (i6A37).
AARS2	Alanine–tRNA ligase, mitochondrial	Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala).
RMND1	Required for meiotic nuclear division protein 1 homolog	Required for mitochondrial translation, possibly by coordinating the assembly or maintenance of the mitochondrial ribosome.
PDHX	Pyruvate dehydrogenase protein X component, mitochondrial	Required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes.
RARS2	Probable arginine–tRNA ligase, mitochondrial	Catalyzes the attachment of arginine to tRNA(Arg) in a two-step reaction: arginine is first activated by ATP to form Arg-AMP and then transferred to the acceptor end of tRNA(Arg).
VARS2	Valine–tRNA ligase, mitochondrial	Catalyzes the attachment of valine to tRNA(Val) in a two-step reaction: valine is first activated by ATP to form Val-AMP and then transferred to the acceptor end of tRNA(Val).
AGK	Acylglycerol kinase, mitochondrial	Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively.
COX4I1	Cytochrome c oxidase subunit 4 isoform 1, mitochondrial	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
TIMM50	Mitochondrial import inner membrane translocase subunit TIM50	Essential component of the TIM23 complex, a complex that mediates the translocation of transit peptide-containing proteins across the mitochondrial inner membrane.
YARS2	Tyrosine–tRNA ligase, mitochondrial	Catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr).
COQ2	4-hydroxybenzoate polyprenyltransferase, mitochondrial	Mediates the second step in the final reaction sequence of coenzyme Q (CoQ) biosynthesis.
DARS2	Aspartate–tRNA ligase, mitochondrial	Catalyzes the attachment of aspartate to tRNA(Asp) in a two-step reaction: aspartate is first activated by ATP to form Asp-AMP and then transferred to the acceptor end of tRNA(Asp).
TTC19	Tetratricopeptide repeat protein 19, mitochondrial	Required for the preservation of the structural and functional integrity of mitochondrial respiratory complex III by allowing the physiological turnover of the Rieske protein UQCRFS1.

Protein-family classification

Druggable: 29 · Difficult: 3 · Unknown: 43 · Druggable fraction: 0.39

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
Enzyme (other)	19	3.0×	6e-05
Kinase	6	2.2×	0.187
Phosphatase	1	1.1×	0.725
Transporter	1	1.0×	0.725
Other/Unknown	43	1.0×	0.725
Protease	2	1.0×	0.725
Transcription factor	3	0.3×	0.996

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC25A4	Other/Unknown	no		MCP, ADT_euk_type, MCP_transmembrane
MRPL49	Other/Unknown	no		Ribosomal_mL49
NARS2	Enzyme (other)	yes	6.1.1.22	Asp/Asn-tRNA-synth_IIb, Aa-tRNA-synt_II, NA-bd_OB_tRNA
DGUOK	Kinase	yes	2.7.1.113	DCK/DGK, P-loop_NTPase, DNK_dom
MT-ATP8	Other/Unknown	no		ATP8_metazoa, ATP8_mammal
MT-TL1	Other/Unknown	no
ATP5F1A	Other/Unknown	no		ATPase_F1/V1/A1_a/bsu_nucl-bd, ATP_synth_asu_C, ATPase_F1/V1/A1_a/bsu_N
TOMM70	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt
MRPL50	Other/Unknown	no		Ribosomal_m50
TIMM22	Other/Unknown	no		TIM22
PYROXD2	Other/Unknown	no		Amino_oxidase, FAD/NAD-bd_sf
PNPLA4	Other/Unknown	no		PNPLA_dom, Acyl_Trfase/lysoPLipase, PLPL
MARS2	Other/Unknown	no		tRNAsynth_Ia_anticodon-bd, Rossmann-like_a/b/a_fold, Met-tRNA_synth
TMEM65	Other/Unknown	no		TMEM65
PDE12	Phosphatase	yes		Endo/exonuclease/phosphatase, Endo/exonu/phosph_ase_sf, PDE12-like_N
DAP3	Other/Unknown	no		Ribosomal_mS29_met, Ribosomal_mS29, P-loop_NTPase
LYRM7	Other/Unknown	no		Complex1_LYR_dom, Complex1_LYR_LYRM7, MZM1/LYRM7
APOO	Other/Unknown	no		MIC26/MIC27, MIC26/MIC27_animal
DLGAP3	Other/Unknown	no		SAPAP
MICOS13	Other/Unknown	no		Mic13
GARS1	Enzyme (other)	yes	6.1.1.14	WHEP-TRS_dom, aa-tRNA-synt_IIb, tRNA-synt_gly
GUK1	Kinase	yes	2.7.4.8	Guanylate_kin-like_dom, GK/Ca_channel_bsu, Guanylate_kinase
NDUFB10	Other/Unknown	no		NADH_UbQ_OxRdtase_su10, NDUFB10
SPG7	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
SURF1	Other/Unknown	no		Surf1/Shy1, Surf1/Surf4
TWNK	Enzyme (other)	yes	3.6.4.12	DNA_helicase_DnaB-like_C, Twinkle-like, P-loop_NTPase
ACO2	Enzyme (other)	yes	4.2.1.3	AconitaseA/IPMdHydase_ssu_swvl, Acoase/IPM_deHydtase_lsu_aba, Aconitase_mito-like
TK2	Kinase	yes	2.7.1.21	DCK/DGK, P-loop_NTPase, DNK_dom
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
TOP3A	Transcription factor	no		Topo_IA, Topo_IA_2, Topo_IA_DNA-bd_dom
TUFM	Other/Unknown	no		T_Tr_GTP-bd_dom, Transl_elong_EFTu/EF1A_C, EFTu-like_2
C1QBP	Other/Unknown	no		MAM33, MAM33_sf
UQCRC2	Protease	yes		Pept_M16_Zn_BS, Peptidase_M16_C, Metalloenz_LuxS/M16
VARS1	Enzyme (other)	yes	6.1.1.9	aa-tRNA-synth_I_CS, aa-tRNA-synth_Ia, Valyl-tRNA_ligase
WARS2	Enzyme (other)	yes	6.1.1.2	aa-tRNA-synth_I_CS, aa-tRNA-synth_Ic, Trp-tRNA-ligase
FBXL4	Other/Unknown	no		F-box_dom, Leu-rich_rpt_Cys-con_subtyp, LRR_dom_sf
MRPL39	Other/Unknown	no		TGS, Beta-grasp_dom_sf, TGS-like
MRPS22	Other/Unknown	no		Ribosomal_mS22
PUS1	Enzyme (other)	yes	5.4.99.B22	PsdUridine_synth_TruA, TruA/RsuA/RluB/E/F_N, PsdUridine_synth_TruA_C
COQ8A	Kinase	yes		ABC1_dom, Kinase-like_dom_sf, ADCK3_dom
RRM2B	Enzyme (other)	yes	1.17.4.1	RNR_small_fam, Ferritin-like_SF, RNR-like
COQ8B	Kinase	yes		ABC1_dom, Kinase-like_dom_sf, ADCK3_dom
MECR	Other/Unknown	no		GroES-like_sf, ADH-like_C, ADH-like_N
TRIT1	Transcription factor	no	2.5.1.75	Matrin/U1-like-C_Znf_C2H2, IPT, P-loop_NTPase
AARS2	Enzyme (other)	yes	6.1.1.7	Ala-tRNA-lgiase_IIc, Transl_B-barrel_sf, tRNA_SAD
RMND1	Other/Unknown	no		DUF155, RMD1/Sad1-interacting
PDHX	Enzyme (other)	yes	1.2.1.104	Biotin_lipoyl, 2-oxoacid_DH_actylTfrase, 2-oxoA_DH_lipoyl-BS
RARS2	Other/Unknown	no		Arg-tRNA-ligase, aa-tRNA-synth_I_CS, DALR_anticod-bd
VARS2	Other/Unknown	no		aa-tRNA-synth_I_CS, aa-tRNA-synth_Ia, Valyl-tRNA_ligase
AGK	Kinase	yes	2.7.1.94	Diacylglycerol_kinase_cat_dom, NAD/diacylglycerol_kinase_sf, ATP-NAD_kinase_N

Expression context

Cohort genes with no expression data: 0.

67 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)	75
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left ventricle myocardium	11
apex of heart	10
adrenal tissue	10
primordial germ cell in gonad	8
heart right ventricle	6
oocyte	6
right adrenal gland	5
gastrocnemius	5
hindlimb stylopod muscle	5
calcaneal tendon	5
right adrenal gland cortex	4
secondary oocyte	4
tibialis anterior	4
deltoid	4
mucosa of transverse colon	4
cerebellar hemisphere	4
right hemisphere of cerebellum	4
skeletal muscle tissue of biceps brachii	3
right frontal lobe	3
endothelial cell	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC25A4	292	ubiquitous	marker	left ventricle myocardium, heart right ventricle, apex of heart
MRPL49	300	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, pancreatic ductal cell
NARS2	278	ubiquitous	marker	secondary oocyte, oocyte, skeletal muscle tissue of biceps brachii
DGUOK	297	ubiquitous	marker	adenohypophysis, olfactory segment of nasal mucosa, pituitary gland
MT-ATP8	134		marker	gastrocnemius, right ovary, right lung
MT-TL1	118	ubiquitous	marker	frontal cortex, right frontal lobe, caudate nucleus
ATP5F1A	295	ubiquitous	marker	heart right ventricle, esophagus squamous epithelium, renal medulla
TOMM70	299	ubiquitous	marker	endothelial cell, gluteal muscle, Brodmann (1909) area 23
MRPL50	254	ubiquitous	marker	left ventricle myocardium, oviduct epithelium, myocardium
TIMM22	134	ubiquitous	marker	apex of heart, primordial germ cell in gonad, heart left ventricle
PYROXD2	240	ubiquitous	marker	right uterine tube, nasal cavity epithelium, right adrenal gland cortex
PNPLA4	276	ubiquitous	marker	oocyte, hindlimb stylopod muscle, diaphragm
MARS2	178	ubiquitous	yes	cardiac muscle of right atrium, left ventricle myocardium, primordial germ cell in gonad
TMEM65	253	ubiquitous	marker	left ventricle myocardium, jejunal mucosa, tibialis anterior
PDE12	272	ubiquitous	yes	mucosa of sigmoid colon, gingival epithelium, epithelium of nasopharynx
DAP3	294	ubiquitous	marker	body of pancreas, adrenal tissue, colonic epithelium
LYRM7	254	ubiquitous	marker	left ventricle myocardium, vastus lateralis, deltoid
APOO	268	ubiquitous	marker	decidua, heart right ventricle, left ventricle myocardium
DLGAP3	150	broad	yes	right frontal lobe, anterior cingulate cortex, nucleus accumbens
MICOS13	254	ubiquitous	marker	apex of heart, left testis, right atrium auricular region
GARS1	293	ubiquitous	marker	secondary oocyte, cartilage tissue, lateral nuclear group of thalamus
GUK1	300	ubiquitous	marker	right frontal lobe, prefrontal cortex, amygdala
NDUFB10	255	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
SPG7	302	ubiquitous	marker	primordial germ cell in gonad, sural nerve, left lobe of thyroid gland
SURF1	183	ubiquitous	marker	apex of heart, body of pancreas, right lobe of liver
TWNK	211	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, tendon of biceps brachii, gastrocnemius
ACO2	291	ubiquitous	marker	heart right ventricle, apex of heart, left ventricle myocardium
TK2	280	ubiquitous	marker	calcaneal tendon, sural nerve, adrenal tissue
MED12	281	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left ovary
TOP3A	134	ubiquitous	yes	blood, ganglionic eminence, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 100.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP5F1A	6,160
TUFM	5,946
VARS1	5,848
IDH2	4,912
DNM1L	4,801
ACO2	4,776
C1QBP	4,534
UQCRC2	4,507
SPG7	3,970
COX4I1	3,929

Intra-cohort edges

A	B	Sources
AARS2	DARS2	string_interaction
AARS2	EARS2	string_interaction
AARS2	GARS1	string_interaction
AARS2	RARS2	biogrid_interaction, string_interaction
AARS2	WARS2	string_interaction
AARS2	YARS2	string_interaction
ABCB7	SURF1	biogrid_interaction
ACO2	IDH2	string_interaction
ACO2	MRPL49	intact
AGK	FBXL4	string_interaction
AGK	SLC25A4	string_interaction
AGK	TIMM22	string_interaction
AGK	TIMM50	string_interaction
APOO	MICOS13	biogrid_interaction, intact, string_interaction
ATG12	TUFM	string_interaction
ATP5F1A	UQCRC2	string_interaction
C1QBP	COQ2	biogrid_interaction
C1QBP	COQ8A	intact
C1QBP	COQ8B	biogrid_interaction
C1QBP	NDUFAF8	biogrid_interaction
C1QBP	UQCRC2	biogrid_interaction
COQ2	COQ8A	string_interaction
COQ2	COQ8B	string_interaction
COQ2	IDH2	intact
COQ2	SLC25A4	biogrid_interaction
COQ8B	TIMM50	biogrid_interaction
COX20	MED12	intact
COX20	SURF1	string_interaction
COX4I1	SURF1	intact
COX4I1	UQCRC2	biogrid_interaction, string_interaction
DAP3	MRPS22	biogrid_interaction, string_interaction
DARS2	EARS2	string_interaction
DARS2	MARS2	string_interaction
DARS2	NARS2	biogrid_interaction
DARS2	RARS2	string_interaction
DARS2	VARS1	string_interaction
DARS2	VARS2	string_interaction
DARS2	WARS2	string_interaction
DARS2	YARS2	string_interaction
EARS2	MARS2	string_interaction
EARS2	NARS2	string_interaction
EARS2	RARS2	string_interaction
EARS2	VARS1	string_interaction
EARS2	VARS2	string_interaction
EARS2	YARS2	intact, string_interaction
FBXL4	RRM2B	string_interaction
FBXL4	TWNK	string_interaction
FOXRED1	NARS2	biogrid_interaction
FOXRED1	NDUFAF6	string_interaction
FOXRED1	NDUFAF8	string_interaction

Structural data

PDB: 43 · AlphaFold-only: 31 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPL49	Q13405	85
MRPL50	Q8N5N7	85
MRPL39	Q9NYK5	85
DAP3	P51398	77
MRPS22	P82650	77
GARS1	P41250	14
GUK1	Q16774	14
TRMT10C	Q7L0Y3	13
DNM1L	O00429	11
IDH2	P48735	11
MT-ATP8	P03928	10
ATP5F1A	P25705	9
NDUFB10	O96000	7
GFER	P55789	7
PUS1	Q9Y606	6
DMD	P11532	6
TUFM	P49411	5
UQCRC2	P22695	5
PDHX	O00330	5
C1QBP	Q07021	4
COQ8A	Q8NI60	4
MECR	Q9BV79	4
ABCB7	O75027	4
TOMM70	O94826	3
PDE12	Q6L8Q7	3
MED12	Q93074	3
RRM2B	Q7LG56	3
AARS2	Q5JTZ9	3
COX4I1	P13073	3
ATG12	O94817	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACO2	Q99798	95.44
PNPLA4	P41247	94.38
SLC25A4	P12235	92.07
LYRM7	Q5U5X0	91.70
NARS2	Q96I59	91.59
PYROXD2	Q8N2H3	91.56
NDUFAF8	A1L188	91.12
FOXRED1	Q96CU9	90.12
EARS2	Q5JPH6	89.84
MARS2	Q96GW9	89.66
RARS2	Q5T160	89.18
PIGY	Q3MUY2	89.02
VARS1	P26640	88.12
VARS2	Q5ST30	87.96
NDUFAF6	Q330K2	87.70
FBXL4	Q9UKA2	86.50
MICOS13	Q5XKP0	86.01
COQ2	Q96H96	85.64
TRIT1	Q9H3H1	85.08
TK2	O00142	85.01
NDUFC2-KCTD14	E9PQ53	84.85
SURF1	Q15526	82.62
TMEM126B	Q8IUX1	82.06
TIMM50	Q3ZCQ8	80.62
TTC19	Q6DKK2	80.28
COQ8B	Q96D53	77.00
APOO	Q9BUR5	74.34
TMEM65	Q6PI78	72.80
RMND1	Q9NWS8	70.28
COX20	Q5RI15	66.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 160. Enrichment computed across 121 evidence-associated genes (95 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 95 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Respiratory electron transport	23	23.0×	2e-23	SURF1, UQCRC2, COX4I1, LYRM7, NDUFAF6, TMEM126B, NDUFAF8, MT-CO1 (+15 more)
Mitochondrial translation termination	21	24.3×	5e-22	MRPL49, MT-ATP8, MRPL39, MRPS22, MRPL50, DAP3, GFM2, MT-ATP6 (+13 more)
Complex I biogenesis	17	29.6×	2e-19	FOXRED1, NDUFAF6, TMEM126B, NDUFAF8, MT-ND1, MT-ND2, MT-ND3, MT-ND4 (+9 more)
Mitochondrial protein degradation	18	21.6×	5e-18	ATP5F1A, SPG7, TWNK, ACO2, UQCRC2, TIMM22, COX4I1, IDH2 (+10 more)
Aerobic respiration and respiratory electron transport	17	15.8×	1e-14	SLC25A4, MT-ATP8, ATP5F1A, SURF1, ACO2, LYRM7, NDUFAF6, TMEM126B (+9 more)
Mitochondrial tRNA aminoacylation	10	54.6×	2e-14	NARS2, WARS2, AARS2, RARS2, VARS2, YARS2, MARS2, DARS2 (+2 more)
tRNA Aminoacylation	10	30.1×	2e-11	NARS2, VARS1, WARS2, AARS2, RARS2, VARS2, YARS2, MARS2 (+2 more)
Translation	16	10.4×	4e-11	MRPL49, NARS2, VARS1, WARS2, MRPL39, MRPS22, MRPL50, AARS2 (+8 more)
Mitochondrial protein import	8	14.1×	1e-06	SLC25A4, ATP5F1A, ACO2, TOMM70, TIMM22, TIMM50, COQ2, GFER
Cristae formation	6	21.9×	4e-06	MT-ATP8, ATP5F1A, APOO, MICOS13, MT-ATP6, ATP5F1D
Metabolism	25	3.1×	4e-06	SLC25A4, MT-ATP8, ATP5F1A, SURF1, ACO2, TK2, MED12, MECR (+17 more)
Mitochondrial translation elongation	8	10.7×	1e-05	MRPL49, TUFM, MRPL39, MRPS22, MRPL50, DAP3, MT-RNR1, OXA1L
Complex IV assembly	6	14.4×	4e-05	SURF1, COX4I1, COX20, MT-CO1, MT-CO2, MT-CO3
Metabolism of proteins	22	2.9×	6e-05	MRPL49, NARS2, ATP5F1A, SPG7, ACO2, VARS1, WARS2, MRPL39 (+14 more)
Mitochondrial translation initiation	7	9.3×	1e-04	MRPL49, MRPL39, MRPS22, MRPL50, DAP3, MT-RNR1, OXA1L
Mitochondrial ribosome-associated quality control	7	9.1×	1e-04	MRPL49, MRPL39, MRPS22, MRPL50, DAP3, MT-RNR1, OXA1L
Formation of ATP by chemiosmotic coupling	4	24.0×	2e-04	MT-ATP8, ATP5F1A, MT-ATP6, ATP5F1D
Mitochondrial biogenesis	6	10.6×	2e-04	MT-ATP8, ATP5F1A, APOO, MICOS13, MT-ATP6, ATP5F1D
Strand-asynchronous mitochondrial DNA replication	3	36.1×	5e-04	TWNK, TOP3A, POLG
Complex III assembly	4	18.5×	5e-04	UQCRC2, TTC19, LYRM7, MT-CYB
Mitochondrial translation	6	8.7×	5e-04	MRPL49, MRPL39, MRPS22, MRPL50, DAP3, GFM2
tRNA modification in the mitochondrion	3	32.8×	6e-04	PUS1, TRIT1, TRMT10C
Protein localization	5	10.0×	9e-04	SLC25A4, ATP5F1A, ACO2, GFER, MPV17
Ubiquinol biosynthesis	3	27.7×	0.001	COQ8A, COQ8B, COQ2
tRNA processing in the mitochondrion	2	48.1×	0.004	TRMT10C, MT-RNR1
TP53 Regulates Metabolic Genes	5	6.8×	0.005	RRM2B, COX4I1, MT-CO1, MT-CO2, MT-CO3
Cytoprotection by HMOX1	4	7.8×	0.010	COX4I1, MT-CO1, MT-CO2, MT-CO3
rRNA processing in the mitochondrion	2	26.7×	0.014	TRMT10C, MT-RNR1
Organelle biogenesis and maintenance	6	4.2×	0.017	MT-ATP8, ATP5F1A, APOO, MICOS13, MT-ATP6, ATP5F1D
3-hydroxyisobutyryl-CoA hydrolase deficiency	1	120.2×	0.044	HIBCH

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 99 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
aerobic respiration	18	45.1×	5e-23	SURF1, UQCRC2, MT-CO1, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L (+10 more)
proton motive force-driven mitochondrial ATP synthesis	17	45.2×	6e-22	MT-ATP8, ATP5F1A, MT-ATP6, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L (+9 more)
mitochondrial respiratory chain complex I assembly	14	58.1×	8e-20	FOXRED1, NDUFAF6, TMEM126B, NDUFAF8, MT-ND1, MT-ND2, MT-ND4, MT-ND5 (+6 more)
mitochondrial electron transport, NADH to ubiquinone	14	50.7×	6e-19	NDUFC2-KCTD14, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, MT-ND6 (+6 more)
cellular respiration	8	34.9×	4e-09	UQCRC2, COX4I1, LYRM7, MT-CO1, MT-CO2, MT-CO3, MT-CYB, NDUFS1
electron transport coupled proton transport	4	170.2×	7e-08	MT-CYB, MT-ND4, MT-ND5, NDUFS7
mitochondrial translation	9	15.8×	3e-07	MRPL49, TUFM, MRPL39, MRPS22, MRPL50, RARS2, DAP3, GFM2 (+1 more)
tRNA aminoacylation for protein translation	5	42.6×	4e-06	VARS1, WARS2, RARS2, MARS2, GARS1
proton motive force-driven ATP synthesis	4	32.4×	3e-04	MT-ATP8, ATP5F1A, MT-ATP6, ATP5F1D
mitochondrial electron transport, cytochrome c to oxygen	4	30.9×	3e-04	COX4I1, MT-CO1, MT-CO2, MT-CO3
valyl-tRNA aminoacylation	2	170.2×	9e-04	VARS1, VARS2
tRNA aminoacylation	2	170.2×	9e-04	YARS2, DARS2
mitochondrial DNA replication	3	46.4×	9e-04	TWNK, RRM2B, POLG
response to copper ion	3	46.4×	9e-04	MT-CO1, MT-CYB, ATP5F1D
protein insertion into mitochondrial inner membrane	3	39.3×	0.001	TOMM70, TIMM22, AGK
response to hypoxia	7	6.8×	0.002	MT-CO1, MT-CO2, MT-CYB, MT-ND1, MT-ND2, MT-ND4, MT-ND5
positive regulation of mitochondrial translation	3	34.0×	0.002	C1QBP, RMND1, TRMT10C
cristae formation	3	31.9×	0.002	APOO, MICOS13, OPA1
ubiquinone biosynthetic process	3	28.4×	0.003	COQ8A, COQ8B, COQ2
generation of precursor metabolites and energy	4	13.9×	0.004	SLC25A4, ACO2, COX4I1, PHKB
inner mitochondrial membrane organization	3	25.5×	0.004	APOO, MICOS13, OPA1
respiratory chain complex IV assembly	2	48.6×	0.012	SURF1, MT-CO3
mitochondrial proton-transporting ATP synthase complex assembly	2	42.6×	0.015	ATP5F1D, OXA1L
mitochondrial ATP synthesis coupled electron transport	2	37.8×	0.018	DGUOK, NDUFV1
peroxisome fission	2	30.9×	0.027	DNM1L, OPA1
regulation of mitochondrial membrane permeability	2	28.4×	0.031	SLC25A4, SPG7
mitochondrial electron transport, ubiquinol to cytochrome c	2	26.2×	0.033	UQCRC2, MT-CYB
negative regulation of defense response to virus	2	26.2×	0.033	C1QBP, ATG12
mitochondrial respiratory chain complex III assembly	2	24.3×	0.038	TTC19, LYRM7
dGDP biosynthetic process	1	170.2×	0.041	GUK1

Therapeutics

Drug target analysis

Approved (phase 4): 7 · Phase ≥3: 9 · Phased (≥1): 11 · Undrugged: 64

Druggability breadth: 55 of 121 evidence-associated genes (45%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MARS2	CHLORAMPHENICOL
TK2	SORIVUDINE
TUFM	GILTERITINIB
COQ8A	FEDRATINIB
COQ8B	FEDRATINIB
GFER	FENOLDOPAM MESYLATE
IDH2	ENASIDENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COQ8A	14	4
GFER	11	4
COQ8B	9	4
IDH2	7	4
MARS2	1	4
PDE12	1	2
GARS1	1	3
TK2	1	4
MED12	1	2
TUFM	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CHLORAMPHENICOL	4	MARS2
SORIVUDINE	4	TK2
GILTERITINIB	4	TUFM
FEDRATINIB	4	COQ8A, COQ8B
VANDETANIB	4	COQ8A, COQ8B
DASATINIB	4	COQ8A
ERLOTINIB	4	COQ8A, COQ8B
CRIZOTINIB	4	COQ8B
FENOLDOPAM MESYLATE	4	GFER
PROMAZINE HYDROCHLORIDE	4	GFER
PROMETHAZINE HYDROCHLORIDE	4	GFER
PHENELZINE SULFATE	4	GFER
PYRITHIONE	4	GFER
DOPAMINE HYDROCHLORIDE	4	GFER
MEPAZINE ACETATE	4	GFER
CHLORPROMAZINE HYDROCHLORIDE	4	GFER
OLANZAPINE	4	GFER
ENASIDENIB	4	IDH2
ENASIDENIB MESYLATE	4	IDH2
IVOSIDENIB	4	IDH2
VORASIDENIB	4	IDH2
OLUTASIDENIB	4	IDH2
CRENOLANIB	3	GARS1
SARACATINIB	3	COQ8A
CANERTINIB	3	COQ8A, COQ8B
TRIAPINE	3	RRM2B
RESVERATROL	3	GFER
MOLIBRESIB	2	MED12, PDE12
TG100-115	2	COQ8A, COQ8B
GALUNISERTIB	2	COQ8A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 25.

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

Symbol	Assays	Type breakdown
COQ8A	93	Binding:93
IDH2	84	Binding:84
COQ8B	77	Binding:77
RRM2B	47	Binding:44, Functional:3
AGK	19	Binding:19
TK2	17	Binding:17
PDE12	9	Binding:9
GARS1	8	Binding:8
VARS1	7	Binding:7
ATP5F1A	6	Binding:6
GUK1	6	Binding:6
MED12	6	Binding:6
PUS1	6	Binding:6
NDUFB10	5	Binding:5
DNM1L	4	Binding:4
HIBCH	4	ADMET:2, Binding:2
TOMM70	2	Binding:2
DAP3	2	Binding:2
TUFM	2	Binding:2
TIMM50	2	Binding:2
SLC25A4	1	Binding:1
DGUOK	1	Binding:1
MT-ATP8	1	Binding:1
MARS2	1	ADMET:1
MICOS13	1	Binding:1
C1QBP	1	Binding:1
UQCRC2	1	Binding:1
MRPS22	1	Binding:1
PDHX	1	Binding:1
RARS2	1	Binding:1
COX4I1	1	Binding:1
GFER	1	Binding:1
ABCB7	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NARS2	6.1.1.22	asparagine-tRNA ligase
DGUOK	2.7.1.113	deoxyguanosine kinase
GARS1	6.1.1.14	glycine-tRNA ligase
GUK1	2.7.4.8	guanylate kinase
SPG7	3.4.24.B18
TWNK	3.6.4.12	DNA helicase
ACO2	4.2.1.3	aconitate hydratase
TK2	2.7.1.21	thymidine kinase
VARS1	6.1.1.9	valine-tRNA ligase
WARS2	6.1.1.2	tryptophan-tRNA ligase
PUS1	5.4.99.B22
RRM2B	1.17.4.1	ribonucleoside-diphosphate reductase
TRIT1	2.5.1.75	tRNA dimethylallyltransferase
AARS2	6.1.1.7	alanine-tRNA ligase
PDHX	1.2.1.104	pyruvate dehydrogenase system
AGK	2.7.1.94	acylglycerol kinase
YARS2	6.1.1.1	tyrosine-tRNA ligase
COQ2	2.5.1.39	4-hydroxybenzoate polyprenyltransferase
DARS2	6.1.1.12	aspartate-tRNA ligase
TRMT10C	2.1.1.218, 2.1.1.221	tRNA (adenine9-N1)-methyltransferase, tRNA (guanine9-N1)-methyltransferase
PIGY	2.4.1.198	phosphatidylinositol N-acetylglucosaminyltransferase
DNM1L	3.6.5.5	dynamin GTPase
GFER	1.8.3.2	thiol oxidase
HIBCH	3.1.2.4	3-hydroxyisobutyryl-CoA hydrolase
IDH2	1.1.1.42	isocitrate dehydrogenase (NADP+)

Pharmacogenomics

Cohort genes with a PharmGKB record: 74; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
CHLORAMPHENICOL	4	MARS2
SORIVUDINE	4	TK2
GILTERITINIB	4	TUFM
FEDRATINIB	4	COQ8A, COQ8B
VANDETANIB	4	COQ8A, COQ8B
DASATINIB	4	COQ8A
ERLOTINIB	4	COQ8A, COQ8B
CRIZOTINIB	4	COQ8B
FENOLDOPAM MESYLATE	4	GFER
PROMAZINE HYDROCHLORIDE	4	GFER
PROMETHAZINE HYDROCHLORIDE	4	GFER
PHENELZINE SULFATE	4	GFER
PYRITHIONE	4	GFER
DOPAMINE HYDROCHLORIDE	4	GFER
MEPAZINE ACETATE	4	GFER
CHLORPROMAZINE HYDROCHLORIDE	4	GFER
OLANZAPINE	4	GFER
ENASIDENIB	4	IDH2
ENASIDENIB MESYLATE	4	IDH2
IVOSIDENIB	4	IDH2
VORASIDENIB	4	IDH2
OLUTASIDENIB	4	IDH2
CRENOLANIB	3	GARS1
SARACATINIB	3	COQ8A
CANERTINIB	3	COQ8A, COQ8B
TRIAPINE	3	RRM2B
RESVERATROL	3	GFER
MOLIBRESIB	2	MED12, PDE12
TG100-115	2	COQ8A, COQ8B
GALUNISERTIB	2	COQ8A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	7	MARS2, TK2, TUFM, COQ8A, COQ8B, GFER, IDH2
B	Phased (≥1) drug, not yet approved	4	PDE12, GARS1, MED12, RRM2B
C	Druggable family + PDB, no drug	16	DGUOK, GUK1, SPG7, TWNK, UQCRC2, WARS2, PUS1, AARS2, PDHX, AGK (+6 more)
D	Druggable family + AlphaFold only, no drug	5	NARS2, ACO2, VARS1, COQ2, PIGY
E	Difficult family or no structure, no drug	43	SLC25A4, MRPL49, MT-ATP8, MT-TL1, ATP5F1A, TOMM70, MRPL50, TIMM22, PYROXD2, PNPLA4 (+33 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ACO2	0	IDH2
WARS2	0	MARS2
MRPS22	1	TUFM
YARS2	0	MARS2
COQ2	0	COQ8A
EARS2	0	MARS2
SLC25A4	1	—
MRPL49	0	—
NARS2	0	—
DGUOK	1	—
MT-ATP8	1	—
MT-TL1	0	—
ATP5F1A	6	—
TOMM70	2	—
MRPL50	0	—
TIMM22	0	—
PYROXD2	0	—
PNPLA4	0	—
TMEM65	0	—
DAP3	2	—
LYRM7	0	—
APOO	0	—
DLGAP3	0	—
MICOS13	1	—
GUK1	6	—
NDUFB10	5	—
SPG7	0	—
SURF1	0	—
TWNK	0	—
TOP3A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 103.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	68
PHASE2	16
PHASE1	10
PHASE3	3
PHASE1/PHASE2	3
PHASE4	1
PHASE2/PHASE3	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03384420	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety and Therapeutic Effects of Transplantation of MNV-BM-BLD in Pediatric Patients With Pearson Syndrome
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy
NCT01694940	Not specified	RECRUITING	North American Mitochondrial Disease Consortium Patient Registry and Biorepository (NAMDC)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT02000284	Not specified	ACTIVE_NOT_RECRUITING	Mitochondrial Dysfunction in Autism Spectrum Disorder
NCT04113447	Not specified	RECRUITING	Mitochondrial Donation: An 18 Month Outcome Study.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DEXTROMETHORPHAN	4	3
CYSTEAMINE BITARTRATE	4	1
ESFLURBIPROFEN	4	1
FLURBIPROFEN	4	1
ICATIBANT	4	1
METFORMIN	4	1
NIACINAMIDE	4	1
PROBUCOL	4	1
REPAGLINIDE	4	1
TRIGLYCERIDES, MEDIUM-CHAIN	4	1
URIDINE TRIACETATE	4	1
SONLICROMANOL	3	5
ELAMIPRETIDE	3	4
VATIQUINONE	3	4
BEZAFIBRATE	3	1
L-CITRULLINE	3	1
MEDIUM-CHAIN TRIGLYCERIDES	3	1
NICOTINAMIDE RIBOSIDE	3	1
NAPAZIMONE	2	4
DOXECITINE	2	1
CHEMBL3739769	0	1