MRPL39

Summary

MRPL39 (mitochondrial ribosomal protein L39, HGNC:14027) is a protein-coding gene on chromosome 21q21.3, encoding Large ribosomal subunit protein mL39 (Q9NYK5). It is a selective cancer dependency (DepMap: 64.9% of cell lines).

Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. Two transcript variants encoding distinct isoforms have been described. A pseudogene corresponding to this gene is found on chromosome 5q.

Source: NCBI Gene 54148 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined oxidative phosphorylation deficiency 59 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 73 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 31
• Cancer dependency (DepMap): dependent in 64.9% of screened cell lines
• MANE Select transcript: NM_017446

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14027
Approved symbol	MRPL39
Name	mitochondrial ribosomal protein L39
Location	21q21.3
Locus type	gene with protein product
Status	Approved
Aliases	RPML5, MRP-L5, MGC104174, PRED66, PRED22, C21orf92, L39mt, MSTP003, MGC3400, FLJ20451, mL39
Ensembl gene	ENSG00000154719
Ensembl biotype	protein_coding
OMIM	611845
Entrez	54148

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 14 protein_coding

ENST00000307301, ENST00000352957, ENST00000419219, ENST00000875588, ENST00000875589, ENST00000925340, ENST00000925341, ENST00000925342, ENST00000925343, ENST00000925344, ENST00000925345, ENST00000925346, ENST00000946900, ENST00000946901

RefSeq mRNA: 2 — MANE Select: NM_017446 NM_017446, NM_080794

CCDS: CCDS13573, CCDS33522

Canonical transcript exons

ENST00000352957 — 10 exons

Exon	Start	End
ENSE00000000141	25607403	25607481
ENSE00001017284	25606449	25606655
ENSE00001017286	25588835	25588882
ENSE00001017292	25597302	25597414
ENSE00001017293	25599799	25599866
ENSE00001017295	25601368	25601467
ENSE00001017296	25593893	25593958
ENSE00001136807	25603796	25603935
ENSE00003605259	25585656	25585754
ENSE00003787201	25592812	25592965

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 93.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.2455 / max 400.1488, expressed in 1814 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
189943	38.2455	1814

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	93.91	gold quality
oocyte	CL:0000023	93.82	gold quality
tendon of biceps brachii	UBERON:0008188	93.80	gold quality
heart left ventricle	UBERON:0002084	93.76	gold quality
cardiac ventricle	UBERON:0002082	93.66	gold quality
right adrenal gland	UBERON:0001233	93.46	gold quality
tendon	UBERON:0000043	93.41	gold quality
calcaneal tendon	UBERON:0003701	93.38	gold quality
right adrenal gland cortex	UBERON:0035827	93.28	gold quality
muscle of leg	UBERON:0001383	93.22	gold quality
gastrocnemius	UBERON:0001388	93.22	gold quality
secondary oocyte	CL:0000655	93.06	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.96	gold quality
muscle organ	UBERON:0001630	92.90	gold quality
left testis	UBERON:0004533	92.88	gold quality
left adrenal gland	UBERON:0001234	92.78	gold quality
rectum	UBERON:0001052	92.75	gold quality
vastus lateralis	UBERON:0001379	92.74	gold quality
quadriceps femoris	UBERON:0001377	92.58	gold quality
testis	UBERON:0000473	92.56	gold quality
heart right ventricle	UBERON:0002080	92.52	gold quality
right testis	UBERON:0004534	92.52	gold quality
diaphragm	UBERON:0001103	92.49	silver quality
body of tongue	UBERON:0011876	92.41	gold quality
heart	UBERON:0000948	92.36	gold quality
left adrenal gland cortex	UBERON:0035825	92.27	gold quality
biceps brachii	UBERON:0001507	92.16	gold quality
adrenal gland	UBERON:0002369	92.13	gold quality
apex of heart	UBERON:0002098	92.07	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.03	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.29

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 64.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 2)

• We found that MRPL39 was significantly downregulated in Gastric Cancer tissues and cell lines and that its expression level was negatively associated with carcinoma size, tumor, lymph node, metastasis (TNM) stage, and lymphatic metastasis. Patients with low MRPL39 expression levels revealed a short overall and disease-free survival period. (PMID:30452299)
• Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease. (PMID:37133451)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mrpl39	ENSDARG00000041570
mus_musculus	Mrpl39	ENSMUSG00000022889
rattus_norvegicus	Mrpl39	ENSRNOG00000047563
drosophila_melanogaster	mRpL39	FBGN0036462
caenorhabditis_elegans		WBGENE00044344

Paralogs (4): TARS1 (ENSG00000113407), TARS2 (ENSG00000143374), PARS2 (ENSG00000162396), TARS3 (ENSG00000185418)

Protein

Protein identifiers

Large ribosomal subunit protein mL39 — Q9NYK5 (reviewed: Q9NYK5)

Alternative names: 39S ribosomal protein L39, mitochondrial, 39S ribosomal protein L5, mitochondrial

All UniProt accessions (2): Q9NYK5, C9JG87

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Component of the mitochondrial large ribosomal subunit (mt-LSU). Mature mammalian 55S mitochondrial ribosomes consist of a small (28S) and a large (39S) subunit. The 28S small subunit contains a 12S ribosomal RNA (12S mt-rRNA) and 30 different proteins. The 39S large subunit contains a 16S rRNA (16S mt-rRNA), a copy of mitochondrial valine transfer RNA (mt-tRNA(Val)), which plays an integral structural role, and 52 different proteins.

Subcellular location. Mitochondrion.

Tissue specificity. Isoform 1 is ubiquitously expressed. Isoform 2 is heart-specific.

Disease relevance. Combined oxidative phosphorylation deficiency 59 (COXPD59) [MIM:620646] An autosomal recessive mitochondrial disease presenting with multisystem manifestations of variable severity. The disease spectrum ranges from lethal infantile Leigh syndrome to a milder disorder characterized by hypertrophic cardiomyopathy, lactic acidosis, attention deficit-hyperactivity disorder, and survival into adulthood. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the mitochondrion-specific ribosomal protein mL39 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NYK5-1	1	yes
Q9NYK5-2	2, MRP-L5V1

RefSeq proteins (2): NP_059142, NP_542984 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004095	TGS	Domain
IPR012675	Beta-grasp_dom_sf	Homologous_superfamily
IPR012676	TGS-like	Homologous_superfamily
IPR018163	Thr/Ala-tRNA-synth_IIc_edit	Homologous_superfamily
IPR050062	Pro-tRNA_synthetase	Family

UniProt features (38 total): strand 16, helix 12, turn 3, sequence variant 2, chain 1, domain 1, modified residue 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

85 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7OF0	ELECTRON MICROSCOPY	2.2
7QI4	ELECTRON MICROSCOPY	2.21
8RRI	ELECTRON MICROSCOPY	2.4
8QU5	ELECTRON MICROSCOPY	2.42
9OLF	ELECTRON MICROSCOPY	2.46
7OF7	ELECTRON MICROSCOPY	2.5
7PO4	ELECTRON MICROSCOPY	2.56
6ZM6	ELECTRON MICROSCOPY	2.59
7O9M	ELECTRON MICROSCOPY	2.6
7OF6	ELECTRON MICROSCOPY	2.6
9CN3	ELECTRON MICROSCOPY	2.62
7QI5	ELECTRON MICROSCOPY	2.63
7OF2	ELECTRON MICROSCOPY	2.7
7OF3	ELECTRON MICROSCOPY	2.7
7OF4	ELECTRON MICROSCOPY	2.7
9PR4	ELECTRON MICROSCOPY	2.77
9PRA	ELECTRON MICROSCOPY	2.83
8ANY	ELECTRON MICROSCOPY	2.85
6ZM5	ELECTRON MICROSCOPY	2.89
7QH7	ELECTRON MICROSCOPY	2.89
7ODR	ELECTRON MICROSCOPY	2.9
7OF5	ELECTRON MICROSCOPY	2.9
8K2A	ELECTRON MICROSCOPY	2.9
8OIT	ELECTRON MICROSCOPY	2.9
9PGL	ELECTRON MICROSCOPY	2.9
9PGF	ELECTRON MICROSCOPY	2.93
6VMI	ELECTRON MICROSCOPY	2.96
6VLZ	ELECTRON MICROSCOPY	2.97
7QI6	ELECTRON MICROSCOPY	2.98
9PSM	ELECTRON MICROSCOPY	2.98

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NYK5-F1	84.76	0.71

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 126

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-5368286	Mitochondrial translation initiation
R-HSA-5389840	Mitochondrial translation elongation
R-HSA-5419276	Mitochondrial translation termination
R-HSA-9937383	Mitochondrial ribosome-associated quality control
R-HSA-392499	Metabolism of proteins
R-HSA-5368287	Mitochondrial translation
R-HSA-72766	Translation

MSigDB gene sets: 254 (showing top): CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GOBP_MITOCHONDRIAL_TRANSLATION, GOBP_TRANSLATION, WEI_MYCN_TARGETS_WITH_E_BOX, MARTINEZ_RB1_TARGETS_UP, GOCC_MITOCHONDRIAL_ENVELOPE, MODULE_207, GOCC_LARGE_RIBOSOMAL_SUBUNIT, GOCC_RIBOSOME, GOCC_ORGANELLAR_RIBOSOME, GOCC_MITOCHONDRIAL_MATRIX, GOCC_ORGANELLE_INNER_MEMBRANE, ZHENG_BOUND_BY_FOXP3, GOCC_RIBOSOMAL_SUBUNIT, GOCC_RIBONUCLEOPROTEIN_COMPLEX

GO Biological Process (1): mitochondrial translation (GO:0032543)

GO Molecular Function (2): nucleotide binding (GO:0000166), RNA binding (GO:0003723)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial ribosome (GO:0005761), mitochondrial large ribosomal subunit (GO:0005762), ribosome (GO:0005840), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Mitochondrial translation	4
Translation	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	1
translation	1
mitochondrial gene expression	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
organellar ribosome	1
mitochondrial matrix	1
organellar large ribosomal subunit	1
mitochondrial ribosome	1
mitochondrial protein-containing complex	1
intracellular membraneless organelle	1
protein-containing complex	1

Protein interactions and networks

STRING

2598 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MRPL39	UXT	Q9UBK9	672
MRPL39	ATP5PF	P18859	620
MRPL39	MRPS31	Q92665	588
MRPL39	MTG1	Q9BT17	569
MRPL39	MRPL1	Q9BYD6	534
MRPL39	RPS9	P46781	533
MRPL39	PPP1R11	O60927	532
MRPL39	MRPL12	P52815	504
MRPL39	MRPL44	Q9H9J2	496
MRPL39	CYYR1	Q96J86	493
MRPL39	MRPL20	Q9BYC9	469
MRPL39	MRPL35	Q9NZE8	467
MRPL39	MRPS15	P82914	460
MRPL39	NUP88	Q99567	448
MRPL39	RPS15	P11174	443

IntAct

114 interactions, top by confidence:

A	B	Type	Score
TEKT2	CEP170	psi-mi:“MI:0914”(association)	0.730
TEFM	POLRMT	psi-mi:“MI:0914”(association)	0.560
NP	KPNA6	psi-mi:“MI:0914”(association)	0.550
MRPL50	GTPBP10	psi-mi:“MI:0914”(association)	0.530
MRPL2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
MRPL13	GTPBP10	psi-mi:“MI:0914”(association)	0.530
MRPL18	GTPBP10	psi-mi:“MI:0914”(association)	0.530
PAK5	OBSL1	psi-mi:“MI:0914”(association)	0.530
NDUFAB1	MIEF1	psi-mi:“MI:0915”(physical association)	0.490
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
Mad2l1	MAD1L1	psi-mi:“MI:0914”(association)	0.350
Gtf3c4	YTHDC1	psi-mi:“MI:0914”(association)	0.350
MRPL50	MRPL43	psi-mi:“MI:0914”(association)	0.350
MRPL9	MRPL43	psi-mi:“MI:0914”(association)	0.350
MRPL1	MRPL43	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
NP	KPNA4	psi-mi:“MI:0914”(association)	0.350
NP	HNRNPDL	psi-mi:“MI:0914”(association)	0.350
NP	KPNA6	psi-mi:“MI:0914”(association)	0.350
NP	TRIM66	psi-mi:“MI:0914”(association)	0.350
KSR1	FAM168B	psi-mi:“MI:0914”(association)	0.350
KSR1		psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350

BioGRID (402): MRPL39 (Affinity Capture-MS), MRPL39 (Affinity Capture-MS), MRPL39 (Affinity Capture-MS), MRPL39 (Affinity Capture-MS), MRPL39 (Affinity Capture-MS), PTCD1 (Affinity Capture-MS), NGRN (Affinity Capture-MS), MRPL45 (Affinity Capture-MS), YARS2 (Affinity Capture-MS), MRPL46 (Affinity Capture-MS), MRPL9 (Affinity Capture-MS), ARMC8 (Affinity Capture-MS), MTERF3 (Affinity Capture-MS), MRPL32 (Affinity Capture-MS), MRPL11 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U3BRC5, A0A2L0VXR5, A2AIL4, A7YVD7, A9UMP7, C5Y210, D3ZN43, E7FCP8, F4I1L3, K2SUY0, M2U578, O43824, O95822, Q08BC6, Q15118, Q16854, Q1LXS2, Q28205, Q2KHV5, Q2QMG2, Q330K2, Q39108, Q4KM93, Q53S58, Q5ZM96, Q6DCC6, Q6JQN1, Q7XYS8, Q8BPE4, Q8K370, Q8N159, Q8R4H7, Q8RWT8, Q8S6N5, Q920F5, Q96RQ3, Q99J39, Q99MR8, Q9BTW9, Q9CWG8

Diamond homologs: B9KAN7, Q9JKF7, Q9NYK5, Q9VUJ0, A5CWF9, A5IJ45, A8F8Q8, B1L7W6, C1DDA6, Q189B8, Q1AWG4, Q47CM4, Q5P7X5, Q7NYC6, Q7VY64, Q7W912, Q7WKF7, Q9WZJ9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MRPL39	“form complex”	“39S mitochondrial large ribosomal subunit”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 123 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitochondrial translation	26	42.1×	1e-34
Mitochondrial ribosome-associated quality control	29	41.9×	3e-38
Mitochondrial translation initiation	27	40.3×	3e-35
Mitochondrial translation elongation	27	40.3×	3e-35
Mitochondrial translation termination	27	34.9×	1e-33
Translation	27	19.7×	2e-26

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial translation	28	44.6×	1e-36
translation	22	20.7×	1e-20

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	49
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1676674	NM_017446.4(MRPL39):c.589-924G>A	Pathogenic
1525985	NM_017446.4(MRPL39):c.896G>T (p.Gly299Val)	Likely pathogenic
3376758	NM_017446.4(MRPL39):c.119T>A (p.Leu40Ter)	Likely pathogenic

SpliceAI

1637 predictions. Top by Δscore:

Variant	Effect	Δscore
21:25593890:TA:T	donor_loss	1.0000
21:25593891:A:AC	donor_gain	1.0000
21:25593891:AC:A	donor_gain	1.0000
21:25593892:C:CG	donor_gain	1.0000
21:25593892:CC:C	donor_gain	1.0000
21:25593892:CCT:C	donor_gain	1.0000
21:25593892:CCTG:C	donor_gain	1.0000
21:25593892:CCTGT:C	donor_gain	1.0000
21:25593954:TGTAC:T	acceptor_gain	1.0000
21:25593955:GTAC:G	acceptor_gain	1.0000
21:25593956:TAC:T	acceptor_gain	1.0000
21:25593957:AC:A	acceptor_gain	1.0000
21:25593958:CC:C	acceptor_gain	1.0000
21:25593959:C:CC	acceptor_gain	1.0000
21:25593959:C:G	acceptor_loss	1.0000
21:25593960:T:C	acceptor_loss	1.0000
21:25593967:C:CT	acceptor_gain	1.0000
21:25593968:A:T	acceptor_gain	1.0000
21:25593970:C:CT	acceptor_gain	1.0000
21:25597295:CACTT:C	donor_loss	1.0000
21:25597296:ACTTA:A	donor_loss	1.0000
21:25597297:CTTAC:C	donor_loss	1.0000
21:25597298:TTACT:T	donor_loss	1.0000
21:25597299:TACT:T	donor_loss	1.0000
21:25597300:A:AC	donor_gain	1.0000
21:25597300:ACTTG:A	donor_gain	1.0000
21:25597301:C:A	donor_loss	1.0000
21:25597301:C:CA	donor_gain	1.0000
21:25597301:CT:C	donor_gain	1.0000
21:25597301:CTT:C	donor_gain	1.0000

AlphaMissense

2231 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:25599850:G:C	F179L	0.995
21:25599850:G:T	F179L	0.995
21:25599852:A:G	F179L	0.995
21:25601464:A:C	Y142D	0.994
21:25603899:G:T	A106D	0.994
21:25599813:A:G	W192R	0.993
21:25599813:A:T	W192R	0.993
21:25601450:A:C	C146W	0.993
21:25606458:A:G	C91R	0.993
21:25606529:A:T	V67D	0.993
21:25592837:C:T	G299D	0.992
21:25606466:G:T	P88H	0.992
21:25592832:A:G	S301P	0.989
21:25601451:C:T	C146Y	0.989
21:25603860:A:G	L119S	0.989
21:25606456:A:C	C91W	0.989
21:25606466:G:C	P88R	0.989
21:25592831:G:A	S301F	0.988
21:25592831:G:T	S301Y	0.988
21:25599811:C:A	W192C	0.988
21:25599811:C:G	W192C	0.988
21:25601455:A:G	S145P	0.988
21:25606454:G:T	A92D	0.988
21:25592838:C:G	G299R	0.987
21:25601452:A:G	C146R	0.987
21:25597326:G:T	A226E	0.986
21:25601459:C:A	W143C	0.984
21:25601459:C:G	W143C	0.984
21:25606455:C:G	A92P	0.984
21:25601457:C:G	R144P	0.983

dbSNP variants (sampled 300 via entrez): RS1000113119 (21:25594777 A>T), RS1000418789 (21:25594498 C>T), RS1000453628 (21:25596442 C>A,G), RS1000618450 (21:25590003 T>C), RS1000668971 (21:25588050 G>A), RS1000766171 (21:25601809 A>C), RS1001144227 (21:25607762 A>G), RS1001257378 (21:25601743 T>C), RS1001366861 (21:25600440 G>A,T), RS1001446135 (21:25594903 T>C), RS1001457328 (21:25595270 T>A), RS1001705153 (21:25601986 T>A), RS1001849758 (21:25604941 G>A), RS1001923153 (21:25605259 C>A,T), RS1002020981 (21:25588236 C>T)

Disease associations

OMIM: gene MIM:611845 | disease phenotypes: MIM:620646, MIM:256000

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation deficiency 59	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Moderate	AR

Mondo (3): mitochondrial disease (MONDO:0044970), combined oxidative phosphorylation deficiency 59 (MONDO:0957992), Leigh syndrome (MONDO:0009723)

Orphanet (2): Mitochondrial disease (Orphanet:68380), Leigh syndrome (Orphanet:506)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000486	Strabismus
HP:0000546	Retinal degeneration
HP:0000741	Apathy
HP:0001081	Cholelithiasis
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001635	Congestive heart failure
HP:0001639	Hypertrophic cardiomyopathy
HP:0002013	Vomiting
HP:0002076	Migraine
HP:0002104	Apnea
HP:0002151	Increased circulating lactate concentration
HP:0002181	Cerebral edema
HP:0002376	Developmental regression
HP:0002928	Decreased activity of the pyruvate dehydrogenase complex
HP:0003215	Dicarboxylic aciduria
HP:0003348	Hyperalaninemia
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0007018	Attention deficit hyperactivity disorder
HP:0007305	CNS demyelination
HP:0008347	Decreased activity of mitochondrial complex IV
HP:0011463	Childhood onset
HP:0011923	Decreased activity of mitochondrial complex I
HP:0011968	Feeding difficulties
HP:0012666	Severely reduced left ventricular ejection fraction
HP:0012707	Elevated brain lactate level by MRS
HP:0012734	Ketotic hypoglycemia

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST005351_14	Carboplatin disposition in epthelial ovarian cancer	9.000000e-06
GCST006988_21	Blond vs. brown/black hair color	2.000000e-09
GCST007600_4	Alzheimer’s disease	3.000000e-07
GCST007600_7	Alzheimer’s disease	4.000000e-07
GCST009391_2004	Metabolite levels	3.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0003924	hair color
EFO:0010347	cholesteryl ester 20:3 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	affects cotreatment, decreases expression	4
bisphenol A	decreases expression, increases methylation, affects cotreatment, affects expression, increases abundance	3
Valproic Acid	increases expression, decreases expression, affects cotreatment	3
bisphenol F	increases expression	1
ginger extract	affects expression, increases abundance, affects cotreatment	1
dicrotophos	decreases expression	1
deoxynivalenol	increases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
avobenzone	increases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
pentabromodiphenyl ether	increases expression	1
cylindrospermopsin	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
bisphenol B	increases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Vorinostat	increases expression	1
Atrazine	increases expression	1
Cisplatin	increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Doxorubicin	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ethyl Methanesulfonate	increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Oils, Volatile	affects cotreatment, affects expression, increases abundance	1

Clinical trials (associated diseases)

112 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
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
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
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
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
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
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
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
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
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
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
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy