DNM1L

Summary

DNM1L (dynamin 1 like, HGNC:2973) is a protein-coding gene on chromosome 12p11.21, encoding Dynamin-1-like protein (O00429). Functions in mitochondrial and peroxisomal division. It is a selective cancer dependency (DepMap: 59.6% of cell lines).

This gene encodes a member of the dynamin superfamily of GTPases. The encoded protein mediates mitochondrial and peroxisomal division, and is involved in developmentally regulated apoptosis and programmed necrosis. Dysfunction of this gene is implicated in several neurological disorders, including Alzheimer’s disease. Mutations in this gene are associated with the autosomal dominant disorder, encephalopathy, lethal, due to defective mitochondrial and peroxisomal fission (EMPF). Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 10059 — RefSeq curated summary.

At a glance

• Gene–disease (curated): encephalopathy due to mitochondrial and peroxisomal fission defect (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 877 total — 29 pathogenic, 32 likely-pathogenic
• Phenotypes (HPO): 109
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 59.6% of screened cell lines
• MANE Select transcript: NM_012062

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2973
Approved symbol	DNM1L
Name	dynamin 1 like
Location	12p11.21
Locus type	gene with protein product
Status	Approved
Aliases	DRP1, DVLP, HDYNIV, DYMPLE, VPS1
Ensembl gene	ENSG00000087470
Ensembl biotype	protein_coding
OMIM	603850
Entrez	10059

Gene structure

Transcript identifiers

Ensembl transcripts: 55 — 28 protein_coding, 16 nonsense_mediated_decay, 11 retained_intron

ENST00000266481, ENST00000358214, ENST00000381000, ENST00000413295, ENST00000434676, ENST00000452533, ENST00000546649, ENST00000546757, ENST00000547078, ENST00000547312, ENST00000547548, ENST00000547640, ENST00000547719, ENST00000547932, ENST00000548151, ENST00000548671, ENST00000548750, ENST00000549157, ENST00000549701, ENST00000549926, ENST00000550011, ENST00000550093, ENST00000550154, ENST00000551076, ENST00000551476, ENST00000551643, ENST00000552743, ENST00000553031, ENST00000553257, ENST00000703337, ENST00000703338, ENST00000703360, ENST00000703361, ENST00000703362, ENST00000703363, ENST00000703364, ENST00000703365, ENST00000703366, ENST00000703367, ENST00000703368, ENST00000703369, ENST00000703370, ENST00000703371, ENST00000703372, ENST00000861255, ENST00000924990, ENST00000924991, ENST00000924992, ENST00000924993, ENST00000945617, ENST00000945618, ENST00000945619, ENST00000945620, ENST00000945621, ENST00000945622

RefSeq mRNA: 8 — MANE Select: NM_012062 NM_001278463, NM_001278464, NM_001278465, NM_001278466, NM_001330380, NM_005690, NM_012062, NM_012063

CCDS: CCDS61095, CCDS61096, CCDS61098, CCDS81680, CCDS8728, CCDS8729, CCDS8730

Canonical transcript exons

ENST00000549701 — 20 exons

Exon	Start	End
ENSE00003459725	32731014	32731134
ENSE00003475538	32737105	32737161
ENSE00003486684	32718643	32718763
ENSE00003523173	32733715	32733807
ENSE00003533077	32738264	32738296
ENSE00003541007	32731356	32731511
ENSE00003547085	32743354	32745650
ENSE00003558641	32722427	32722633
ENSE00003563316	32742589	32742748
ENSE00003573157	32701415	32701562
ENSE00003574572	32707367	32707413
ENSE00003592430	32731854	32731943
ENSE00003625373	32740409	32740518
ENSE00003625693	32710929	32711015
ENSE00003635339	32713209	32713371
ENSE00003669383	32740064	32740240
ENSE00003693523	32708153	32708224
ENSE00003791700	32720664	32720795
ENSE00003988764	32679301	32679465
ENSE00003988786	32737865	32737942

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.9605 / max 315.7795, expressed in 1801 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125004	23.5986	1801
125003	0.3618	169

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	98.76	gold quality
substantia nigra pars compacta	UBERON:0001965	98.52	gold quality
sperm	CL:0000019	98.46	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.39	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.97	gold quality
lateral globus pallidus	UBERON:0002476	97.96	gold quality
parietal lobe	UBERON:0001872	97.73	gold quality
superior vestibular nucleus	UBERON:0007227	97.71	gold quality
postcentral gyrus	UBERON:0002581	97.68	gold quality
entorhinal cortex	UBERON:0002728	97.66	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.61	gold quality
cerebellar hemisphere	UBERON:0002245	97.59	gold quality
middle temporal gyrus	UBERON:0002771	97.57	gold quality
cerebellar cortex	UBERON:0002129	97.56	gold quality
cortical plate	UBERON:0005343	97.38	gold quality
superior frontal gyrus	UBERON:0002661	97.35	gold quality
saphenous vein	UBERON:0007318	97.15	gold quality
pons	UBERON:0000988	97.14	gold quality
adrenal tissue	UBERON:0018303	96.77	gold quality
trigeminal ganglion	UBERON:0001675	96.75	gold quality
biceps brachii	UBERON:0001507	96.72	gold quality
cerebellum	UBERON:0002037	96.59	gold quality
corpus callosum	UBERON:0002336	96.59	gold quality
ventral tegmental area	UBERON:0002691	96.58	gold quality
cauda epididymis	UBERON:0004360	96.58	gold quality
primary visual cortex	UBERON:0002436	96.54	gold quality
male germ cell	CL:0000015	96.50	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.28	gold quality
ganglionic eminence	UBERON:0004023	96.24	gold quality
endothelial cell	CL:0000115	96.23	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.69

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, DDIT3, NCOA2, TAF1, TP53, VPS35

miRNA regulators (miRDB)

164 targeting DNM1L, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 59.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• contributes to mitochondrial division in mammalian cells (PMID:11514614)
• role in peroxisomal fission (PMID:12499366)
• DNM1L performs an essential but transient role in peroxisome division (PMID:12618434)
• This protein mediates scission of the outer mitochondrial membrane, resulting in fragmentation and fission of the mitochondrial network. Inhibition of Drp1 prevented p20-induced fission of mitochondria. (PMID:12668660)
• DLP1 has a role in mitochondrial fission through an interaction with hFis1 (PMID:12861026)
• Minimal HdynIV promoter has been characterized and shown that CTCCCAGCA (-108 to -100) sequence may act as a novel transcriptional element for regulating HdynIV gene expression. (PMID:14741701)
• Fis1, Drp1, and Opa1 have roles in apoptosis (PMID:15356267)
• GTPase domain of DLP1 provides an enzymatic function, other domains contain information for assembly and mitochondrial targeting (PMID:15364948)
• Data show that BIK activates recruitment of DRP1 to the surface of the endoplasmic reticulum in intact cells, resulting in mitochondrial fragmentation but little release of cytochrome c to the cytosol. (PMID:15791210)
• Early regulatory GTPase-like function of dynamin precedes late, assembly-dependent steps during which GTP hydrolysis is required for vesicle release. (PMID:15824135)
• Drp1 together with mitochondrial fission protein (hFis1) antogonizes Bcl-2. (PMID:16010987)
• phosphorylation of Drp1 on Ser-585 promotes mitochondrial fission in mitotic cells (PMID:17301055)
• Dnregulation of Drp1 delays but does not inhibit apoptosis, suggesting that mitochondrial fragmentation is not a prerequisite for apoptosis. (PMID:17332775)
• Protein phosphorylation at Ser(637) results in clear alterations in Drp1 function and mitochondrial morphology. (PMID:17553808)
• MARCH5 is required for DRP1-dependent mitochondrial division. (PMID:17606867)
• Results show that Drp1 mediates caspase-independent type III cell death in normal and leukemic cells. (PMID:17682056)
• Precise interactions between a few proteins are required for mitochondrial fusion and division. Among them Drp1, Mfn1, Mfn2 and Opal are considered the most important. (PMID:17718388)
• Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. (PMID:17721437)
• Drp1 dephosphorylation increases cell vulnerability to apoptosis. (PMID:17906671)
• review of the regulation, activity, and function of dynamin-related protein 1, the main factor for controlled mitochondrial fission [review] (PMID:18465792)
• The majority of mutations responsible for autosomatic dominant optic atrophy are localized in OPA1 gene. Second locus is linked to 18q12.2-q12.3 (OPA4) and a third locus on 22q12.1-q13.1 (OPA5). (PMID:18488399)
• DLP1 reduction causes mitochondrial abnormalities in sAD fibroblasts, elevated oxidative stress and increased amyloid beta production are likely the potential pathogenic factors that cause DLP1 reduction and abnormal mitochondrial distribution (PMID:18599615)
• CaMKIalpha is a widely expressed protein kinase, suggesting that Ca2+ is likely to be functionally important in the control of mitochondrial dynamics through regulation of Drp1 phosphorylation in neurons and other cell types. (PMID:18695047)
• fragmentation of depolarized mitochondria depends on a loop involving sustained Ca(2+) rise, activation of calcineurin, and dephosphorylation of Drp1 and its translocation to the organelle (PMID:18838687)
• DLP1 also caused global morphological changes in mitochondrial outer membrane-like liposomes, but DLP1 did not stimulate BAX-permeabilizing function in the absence or presence of Bif-1. (PMID:19074440)
• study found nitric oxide produced in response to beta-amyloid protein triggered mitochondrial fission & neuronal damage, in part by S-nitrosylation of drp1; SNO-Drp1 is increased in Alzheimer disease patients brains (PMID:19342591)
• Results suggest that Drp1 appears to affect the activity of the mitochondrial fusion machinery by unbalancing the protein levels of mitofusins and OPA1. (PMID:19409380)
• Drp1 is dephosphorylated in PINK1 deficient cells due to activation of the calcium-dependent phosphatase calcineurin. (PMID:19492085)
• Nuclear DRP1 is highly expressed in lung adenocarcinomas, and correlates with poor prognosis. (PMID:19525928)
• lack of MARCH5 results in mitochondrial elongation, which promotes cellular senescence by blocking Drp1 activity and/or promoting accumulation of Mfn1 at the mitochondria (PMID:20103533)
• There is a Drp1- and Fis1-induced, and PINK1-mediated protection mechanism in senescent cells. (PMID:20179104)
• we observed that increasing mitochondrial calcium induced mitochondrial fragmentation, which correlated with the presence of Drp1 (PMID:20428767)
• inhibition of mitochondrial fission, with the consequent formation of a mitochondrial network, is required for myogenic differentiation and is dependent on inhibition of Drp1 function. also, nitric oxide inhibits Drp1-dependent mitochondrial fission (PMID:20467441)
• Drp1 has a role in dynamic regulation of mitochondrial fission [review] (PMID:20649536)
• Data suggest that Bax activation is not essential for mitochondrial outer membrane permeabilization but essential for Drp1-mediated mitochondrial fission during the apoptosis caused by Photofrin-PDT. (PMID:20683914)
• Data suggest that the Drp1 A395D lethal defect likely resulted in impaired higher order assembly of Drp1 at mitochondria, leading to decreased fission, elongated mitochondria, and altered cellular distribution of mitochondria. (PMID:20696759)
• Using a minimal cell-free assay study identified Drp1 as a protein capable of stimulating oligomerization of Bax upon its insertion into liposomes and provides evidence that Drp1 stimulates Bax oligomerization by promoting membrane remodeling. (PMID:20850011)
• Mutant proteins of neurodegenerative diseases interact with Drp1, activate mitochondrial fission machinery, fragment mitochondria excessively, and impair mitochondrial transport and mitochondrial dynamics. (PMID:21145355)
• Endophilin and dynamin colocalize at the base of the clathrin coat. (PMID:21172823)
• Drp1 as a novel substrate of Parkin and suggest a potential mechanism linking abnormal Parkin expression to mitochondrial dysfunction in the pathogenesis of Parkinson disease. (PMID:21292769)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dnm1l	ENSDARG00000015006
mus_musculus	Dnm1l	ENSMUSG00000022789
rattus_norvegicus	Dnm1l	ENSRNOG00000001813

Paralogs (6): DNM2 (ENSG00000079805), DNM1 (ENSG00000106976), MX1 (ENSG00000157601), MX2 (ENSG00000183486), DNM3 (ENSG00000197959), OPA1 (ENSG00000198836)

Protein

Protein identifiers

Dynamin-1-like protein — O00429 (reviewed: O00429)

Alternative names: Dnm1p/Vps1p-like protein, Dynamin family member proline-rich carboxyl-terminal domain less, Dynamin-like protein, Dynamin-like protein 4, Dynamin-like protein IV, Dynamin-related protein 1

All UniProt accessions (24): O00429, A0A8V8TQT5, A0A8V8TQV1, A0A8V8TRA9, A0A994J3F1, A0A994J3G1, A0A994J3G5, A0A994J3M8, A0A994J402, A0A994J409, A0A994J691, A0A994J696, A0A994J6A0, A0A994J6L3, A0A994J6L8, B4DDQ3, B4DPZ9, F8VR28, F8VUJ9, F8VYL3, F8VZ52, F8W1W3, H0YHY4, H0YI79

UniProt curated annotations — full annotation on UniProt →

Function. Functions in mitochondrial and peroxisomal division. Mediates membrane fission through oligomerization into membrane-associated tubular structures that wrap around the scission site to constrict and sever the mitochondrial membrane through a GTP hydrolysis-dependent mechanism. The specific recruitment at scission sites is mediated by membrane receptors like MFF, MIEF1 and MIEF2 for mitochondrial membranes. While the recruitment by the membrane receptors is GTP-dependent, the following hydrolysis of GTP induces the dissociation from the receptors and allows DNM1L filaments to curl into closed rings that are probably sufficient to sever a double membrane. Acts downstream of PINK1 to promote mitochondrial fission in a PRKN-dependent manner. Plays an important role in mitochondrial fission during mitosis. Through its function in mitochondrial division, ensures the survival of at least some types of postmitotic neurons, including Purkinje cells, by suppressing oxidative damage. Required for normal brain development, including that of cerebellum. Facilitates developmentally regulated apoptosis during neural tube formation. Required for a normal rate of cytochrome c release and caspase activation during apoptosis; this requirement may depend upon the cell type and the physiological apoptotic cues. Required for formation of endocytic vesicles. Proposed to regulate synaptic vesicle membrane dynamics through association with BCL2L1 isoform Bcl-X(L) which stimulates its GTPase activity in synaptic vesicles; the function may require its recruitment by MFF to clathrin-containing vesicles. Required for programmed necrosis execution. Rhythmic control of its activity following phosphorylation at Ser-637 is essential for the circadian control of mitochondrial ATP production. Inhibits peroxisomal division when overexpressed. Inhibits peroxisomal division when overexpressed.

Subunit / interactions. Homotetramer; dimerizes through the N-terminal GTP-middle region of one molecule binding to the GED domain of another DNM1L molecule. Oligomerizes in a GTP-dependent manner to form membrane-associated tubules with a spiral pattern. Interacts with GSK3B and MARCHF5. Interacts (via the GTPase and B domains) with UBE2I; the interaction promotes sumoylation of DNM1L, mainly in its B domain. Interacts with PPP3CA; the interaction dephosphorylates DNM1L and regulates its transition to mitochondria. Interacts with BCL2L1 isoform BCL-X(L) and CLTA; DNM1L and BCL2L1 isoform BCL-X(L) may form a complex in synaptic vesicles that also contains clathrin and MFF. Interacts with MFF; the interaction is inhibited by C11orf65/MFI. Interacts with FIS1; may form part of a larger protein complex at the endoplasmic reticulum-mitochondrial interface during mitochondrial fission. Interacts with CANX. Interacts with BCAP31. Interacts with MIEF2 and MIEF1; GTP-dependent, regulates GTP hydrolysis and DNM1L oligomerization. Interacts with PGAM5; this interaction leads to dephosphorylation at Ser-656 and activation of GTPase activity and eventually to mitochondria fragmentation. Interacts with RALBP1; during mitosis, recruits DNM1L to the mitochondrion and mediates its activation by the mitotic kinase cyclin B-CDK1. Interacts with FUNDC1; this interaction recruits DNM1L/DRP1 at ER-mitochondria contact sites.

Subcellular location. Cytoplasm. Cytosol. Golgi apparatus. Endomembrane system. Mitochondrion outer membrane. Peroxisome. Membrane. Clathrin-coated pit. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle membrane.

Tissue specificity. Ubiquitously expressed with highest levels found in skeletal muscles, heart, kidney and brain. Isoform 1 is brain-specific. Isoform 2 and isoform 3 are predominantly expressed in testis and skeletal muscles respectively. Isoform 4 is weakly expressed in brain, heart and kidney. Isoform 5 is dominantly expressed in liver, heart and kidney. Isoform 6 is expressed in neurons.

Post-translational modifications. Phosphorylation/dephosphorylation events on two sites near the GED domain regulate mitochondrial fission. Phosphorylation on Ser-637 by CAMK1 and PKA inhibits the GTPase activity, leading to a defect in mitochondrial fission promoting mitochondrial elongation. Dephosphorylated on this site by PPP3CA which promotes mitochondrial fission. Phosphorylation on Ser-616 by CDK1 and PINK1 activates the GTPase activity and promotes mitochondrial fission. Phosphorylated in a circadian manner at Ser-637. Dephosphorylated by PGAM5. Sumoylated on various lysine residues within the B domain, probably by MUL1. Sumoylation positively regulates mitochondrial fission. Desumoylated by SENP5 during G2/M transition of mitosis. Appears to be linked to its catalytic activity. S-nitrosylation increases DNM1L dimerization, mitochondrial fission and causes neuronal damage. Ubiquitination by MARCHF5 affects mitochondrial morphology. O-GlcNAcylation augments the level of the GTP-bound active form of DNM1L and induces translocation from the cytoplasm to mitochondria in cardiomyocytes. It also decreases phosphorylation at Ser-637.

Disease relevance. May be associated with Alzheimer disease through amyloid-beta-induced increased S-nitrosylation of DNM1L, which triggers, directly or indirectly, excessive mitochondrial fission, synaptic loss and neuronal damage. Encephalopathy due to defective mitochondrial and peroxisomal fission 1 (EMPF1) [MIM:614388] A rare autosomal dominant systemic disorder resulting in lack of neurologic development and death in infancy. After birth, infants present in the first week of life with poor feeding and neurologic impairment, including hypotonia, little spontaneous movement, no tendon reflexes, no response to light stimulation, and poor visual fixation. Other features include mildly elevated plasma concentration of very-long-chain fatty acids, lactic acidosis, microcephaly, deep-set eyes, optic atrophy and hypoplasia, and an abnormal gyral pattern in both frontal lobes associated with dysmyelination. The disease is caused by variants affecting the gene represented in this entry. Optic atrophy 5 (OPA5) [MIM:610708] A form of optic atrophy, a disease characterized by progressive visual loss in association with a deficiency in the number of nerve fibers which arise in the retina and converge to form the optic disk, optic nerve, optic chiasm and optic tracts. OPA5 is an autosomal dominant non-syndromic form that manifests as slowly progressive visual loss with variable onset from the first to third decades. Additional ocular abnormalities may include central scotoma and dyschromatopsia. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. GTPase activity is increased by binding to phospholipid membranes.

Domain organisation. The GED domain folds back to interact, in cis, with the GTP-binding domain and middle domain, and interacts, in trans, with the GED domains of other DNM1L molecules, and is thus critical for activating GTPase activity and for DNM1L dimerization.

Similarity. Belongs to the TRAFAC class dynamin-like GTPase superfamily. Dynamin/Fzo/YdjA family.

Isoforms (9)

UniProt ID	Names	Canonical?
O00429-1	1, HdynIV-WT, DLP1F	yes
O00429-2	4, HdynIV-11, DLP1c
O00429-3	2, DLP1a
O00429-4	3, HdynIV-37, DLP1b
O00429-5	5, HdynIV-26
O00429-6	6
O00429-7	7
O00429-8	8
O00429-9	9

RefSeq proteins (8): NP_001265392, NP_001265393, NP_001265394, NP_001265395, NP_001317309, NP_005681, NP_036192, NP_036193 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000375	Dynamin_stalk	Domain
IPR001401	Dynamin_GTPase	Domain
IPR003130	GED	Domain
IPR019762	Dynamin_GTPase_CS	Conserved_site
IPR020850	GED_dom	Domain
IPR022812	Dynamin	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR030381	G_DYNAMIN_dom	Domain
IPR045063	Dynamin_N	Domain

Pfam: PF00350, PF01031, PF02212

Enzyme classification (BRENDA):

• EC 3.6.5.5 — dynamin GTPase (BRENDA: 23 organisms, 104 substrates, 250 inhibitors, 42 Km, 26 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	0.0034–2.115	37
ATP	0.2	1

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (142 total): mutagenesis site 40, helix 30, strand 15, region of interest 10, sequence variant 10, modified residue 8, cross-link 8, splice variant 7, turn 3, binding site 3, domain 2, compositionally biased region 2, glycosylation site 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
3W6P	X-RAY DIFFRACTION	1.7
3W6O	X-RAY DIFFRACTION	1.9
3W6N	X-RAY DIFFRACTION	2
4H1U	X-RAY DIFFRACTION	2.3
4H1V	X-RAY DIFFRACTION	2.3
8SKN	X-RAY DIFFRACTION	2.41
9N7Z	X-RAY DIFFRACTION	2.51
4BEJ	X-RAY DIFFRACTION	3.48
5WP9	ELECTRON MICROSCOPY	4.22
8T1H	ELECTRON MICROSCOPY	5.97
8V8T	ELECTRON MICROSCOPY	14.73

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00429-F1	77.09	0.32

Functional residue map

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

Ligand- & substrate-binding residues (3): 32–40; 215–221; 246–249

Post-translational modifications (16): 1, 529, 548, 597, 607, 616, 637, 644, 532, 535, 558, 568, 594, 597, 606, 608

Glycosylation sites (2): 585, 586

Mutagenesis-validated functional residues (40):

Position	Phenotype
34	abolishes gtp hydrolysis.
38	loss of gtpase activity. impairs mitochondrial division and induces changes in peroxisome morphology. no effect on oligo
38	overexpression delays protein secretion. rescues fragmented or truncated mitochondria in prkn- or pink1-depleted cells.
39	abolishes gtp hydrolysis.
39	decreased localization to the perinuclear region.
39	reduces peroxisomal abundance.
41	temperature-sensitive. impairs mitochondrial division.
59	abolishes gtp hydrolysis. impairs mitochondrial division. reduces peroxisomal abundance.
146	abolishes gtp hydrolysis.
149	abolishes gtp hydrolysis.
190	unable to homooligomerize. unable to associate with mief2 into filaments forming the tubular structures that wrap around
216	abolishes gtp hydrolysis.
218	abolishes gtp hydrolysis.
221	unable to homooligomerize. unable to associate with mief2 into filaments forming the tubular structures that wrap around
281	temperature-sensitive. impairs mitochondrial division.
300	no effect on s-nitrosylation.
345	no effect on s-nitrosylation.
361	no effect on s-nitrosylation.
367	no effect on s-nitrosylation.
401–404	impairs formation of higher order oligomers, but not homodimerization.
431	no effect on s-nitrosylation.
446	no effect on s-nitrosylation.
470	no effect on s-nitrosylation.
490	does not impair homodimerization and formation of higher order oligomers.
490	impairs homodimerization and formation of higher order oligomers.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-75153	Apoptotic execution phase

MSigDB gene sets: 545 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_POSITIVE_REGULATION_OF_MITOCHONDRIAL_FISSION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOMF_GTPASE_BINDING, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_LEUKOCYTE_MIGRATION

GO Biological Process (25): mitochondrial fission (GO:0000266), calcium ion transport (GO:0006816), endocytosis (GO:0006897), mitochondrion organization (GO:0007005), regulation of gene expression (GO:0010468), peroxisome fission (GO:0016559), mitochondrial fragmentation involved in apoptotic process (GO:0043653), intracellular distribution of mitochondria (GO:0048312), rhythmic process (GO:0048511), positive regulation of protein secretion (GO:0050714), protein complex oligomerization (GO:0051259), heart contraction (GO:0060047), protein localization to mitochondrion (GO:0070585), positive regulation of neutrophil chemotaxis (GO:0090023), positive regulation of mitochondrial fission (GO:0090141), mitochondrial membrane fission (GO:0090149), mitocytosis (GO:0160040), regulation of peroxisome organization (GO:1900063), regulation of mitophagy (GO:1901524), regulation of ATP metabolic process (GO:1903578), regulation of mitochondrion organization (GO:0010821), programmed cell death (GO:0012501), metal ion transport (GO:0030001), mitochondrion distribution (GO:0048311), positive regulation of secretion by cell (GO:1903532)

GO Molecular Function (13): GTPase activity (GO:0003924), GTPase activator activity (GO:0005096), GTP binding (GO:0005525), microtubule binding (GO:0008017), lipid binding (GO:0008289), GTP-dependent protein binding (GO:0030742), small GTPase binding (GO:0031267), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (19): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), peroxisome (GO:0005777), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cytosol (GO:0005829), microtubule (GO:0005874), brush border (GO:0005903), clathrin-coated pit (GO:0005905), membrane (GO:0016020), synaptic vesicle membrane (GO:0030672), protein-containing complex (GO:0032991), perinuclear region of cytoplasm (GO:0048471), endomembrane system (GO:0012505), cytoplasmic vesicle (GO:0031410), synapse (GO:0045202), mitochondrion-derived vesicle (GO:0099073)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Apoptosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	6
cellular anatomical structure	5
intracellular membrane-bounded organelle	3
endomembrane system	3
organelle fission	2
peroxisome organization	2
mitochondrion distribution	2
mitochondrial fission	2
binding	2
protein binding	2
mitochondrion organization	1
metal ion transport	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
organelle organization	1
gene expression	1
regulation of macromolecule biosynthetic process	1
apoptotic mitochondrial changes	1
biological_process	1
protein secretion	1
regulation of protein secretion	1
positive regulation of protein transport	1
positive regulation of secretion by cell	1
protein-containing complex assembly	1
heart process	1
blood circulation	1
protein localization to organelle	1
neutrophil chemotaxis	1
positive regulation of granulocyte chemotaxis	1
regulation of neutrophil chemotaxis	1
positive regulation of neutrophil migration	1
positive regulation of organelle organization	1
positive regulation of developmental process	1
regulation of mitochondrial fission	1
membrane fission	1
establishment of mitochondrion localization	1
migracytosis	1
regulation of organelle organization	1

Protein interactions and networks

STRING

4185 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNM1L	FIS1	Q9Y3D6	999
DNM1L	MFF	Q9GZY8	998
DNM1L	MIEF2	Q96C03	997
DNM1L	MIEF1	Q9NQG6	996
DNM1L	MFN2	O95140	976
DNM1L	MARCHF5	Q9NX47	951
DNM1L	MFN1	Q8IWA4	938
DNM1L	FUNDC1	Q8IVP5	936
DNM1L	PEX11A	O75192	909
DNM1L	PGAM5	Q96HS1	908
DNM1L	MTFP1	Q9UDX5	900
DNM1L	PINK1	Q9BXM7	898
DNM1L	CYCS	P00001	856
DNM1L	VPS35	Q96QK1	846
DNM1L	PEX11B	O96011	835

IntAct

198 interactions, top by confidence:

A	B	Type	Score
LRRK2	DNM1L	psi-mi:“MI:0915”(physical association)	0.910
DNM1L	LRRK2	psi-mi:“MI:0403”(colocalization)	0.910
DNM1L	LRRK2	psi-mi:“MI:0915”(physical association)	0.910
LRRK2	DNM1L	psi-mi:“MI:0403”(colocalization)	0.910
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
DNM1L	MIEF2	psi-mi:“MI:0915”(physical association)	0.700
DNM1L	MIEF2	psi-mi:“MI:0914”(association)	0.700
MIEF2	DNM1L	psi-mi:“MI:0403”(colocalization)	0.700
DNM1L	MIEF1	psi-mi:“MI:0915”(physical association)	0.690
MIEF1	DNM1L	psi-mi:“MI:0914”(association)	0.690
MIEF1	DNM1L	psi-mi:“MI:0915”(physical association)	0.690
MIEF1	DNM1L	psi-mi:“MI:0403”(colocalization)	0.690

BioGRID (418): MAGEA1 (Two-hybrid), MAGEA3 (Two-hybrid), RRM2 (Two-hybrid), SCG3 (Two-hybrid), SH3GL1 (Two-hybrid), ZBTB24 (Reconstituted Complex), DNM1L (Biochemical Activity), FZR1 (Reconstituted Complex), DNM1L (Affinity Capture-MS), DNM1L (Affinity Capture-MS), DNM1L (Affinity Capture-MS), DNM1L (Affinity Capture-MS), DNM1L (Affinity Capture-MS), DNM1L (Affinity Capture-RNA), ATIC (Co-fractionation)

ESM2 similar proteins: A1E2I4, A1E2I5, A6H7I5, A7VK00, O00429, O35303, P09922, P18589, P18590, P20591, P20592, P21575, P21576, P27619, P33237, P39052, P39053, P39054, P39055, P42697, P50570, P79135, Q000A9, Q05193, Q08877, Q08DF4, Q28379, Q2KIA5, Q2KTC2, Q39821, Q39828, Q4U4N4, Q5I2P5, Q5R5G3, Q61107, Q6PW23, Q6TKS7, Q6TN15, Q7SXN5, Q7T2P0

Diamond homologs: A0MWD1, A1E2I4, A1E2I5, A6H7I5, A7VK00, G0SGC7, O00429, O35303, O60313, P09922, P18588, P18589, P18590, P20591, P20592, P20593, P21575, P27594, P27619, P32266, P33237, P33238, P39052, P39053, P39054, P39055, P42697, P50570, P54861, P58281, P79135, P87320, Q000A9, Q05193, Q08877, Q08DF4, Q28379, Q2KIA5, Q2KTC2, Q3UD61

SIGNOR signaling

41 interactions.

A	Effect	B	Mechanism
PRKCD	up-regulates	DNM1L	phosphorylation
MFF	“up-regulates activity”	DNM1L	relocalization
PPP3CB	“up-regulates activity”	DNM1L	dephosphorylation
PPP3CC	“up-regulates activity”	DNM1L	dephosphorylation
PPP3CA	“up-regulates activity”	DNM1L	dephosphorylation
Calcineurin	“up-regulates activity”	DNM1L	dephosphorylation
PP2B	“up-regulates activity”	DNM1L	dephosphorylation
MARCHF5	“down-regulates quantity by destabilization”	DNM1L	polyubiquitination
DNM1L	up-regulates	Mitochondrial_fission
FZR1	“down-regulates quantity”	DNM1L	ubiquitination
MUL1	“up-regulates activity”	DNM1L	sumoylation
CyclinB/CDK1	“up-regulates activity”	DNM1L	phosphorylation
PDCD1	“down-regulates activity”	DNM1L
ERK1/2	“up-regulates activity”	DNM1L	phosphorylation
MTOR	“up-regulates activity”	DNM1L	phosphorylation
LRRK2	“up-regulates activity”	DNM1L	phosphorylation
GSK3B	“up-regulates activity”	DNM1L	phosphorylation
ABL1	“up-regulates activity”	DNM1L	phosphorylation
CDK5	“up-regulates activity”	DNM1L	phosphorylation
PRKN	“down-regulates quantity”	DNM1L	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 166 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
Activation of BAD and translocation to mitochondria	7	48.5×	7e-09
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	42.8×	1e-08
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	42.8×	1e-08
Activation of BH3-only proteins	7	31.6×	1e-07
Intrinsic Pathway for Apoptosis	10	26.6×	2e-09
RHO GTPases activate PKNs	7	20.2×	3e-06
FOXO-mediated transcription	6	18.3×	4e-05
Apoptosis	11	16.8×	7e-09

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of mitochondrial fission	5	26.2×	5e-04
positive regulation of protein targeting to membrane	6	23.1×	1e-04
cellular response to reactive oxygen species	7	19.7×	8e-05
protein targeting	5	12.6×	8e-03
positive regulation of miRNA transcription	6	11.9×	3e-03
intracellular protein localization	10	7.2×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	29
Likely pathogenic	32
Uncertain significance	321
Likely benign	367
Benign	70

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1320222	NM_012062.5(DNM1L):c.1227_1228del (p.Glu410fs)	Pathogenic
1367559	NM_012062.5(DNM1L):c.1034del (p.Cys345fs)	Pathogenic
1395392	NM_012062.5(DNM1L):c.1945C>T (p.Arg649Ter)	Pathogenic
1455176	NC_000012.11:g.(?32729292)(33049665_?)del	Pathogenic
1456963	NM_012062.5(DNM1L):c.1908_1911dup (p.Ala638fs)	Pathogenic
1460297	NC_000012.11:g.(?32866123)(32866325_?)del	Pathogenic
214313	NM_012062.5(DNM1L):c.1207C>T (p.Arg403Cys)	Pathogenic
253262	NM_012062.5(DNM1L):c.1084G>A (p.Gly362Ser)	Pathogenic
253263	NM_001278464.2(DNM1L):c.261dup (p.Trp88fs)	Pathogenic
2737258	NM_012062.5(DNM1L):c.1365dup (p.Arg456fs)	Pathogenic
2767526	NM_012062.5(DNM1L):c.496del (p.Ile166fs)	Pathogenic
3023647	NM_012062.5(DNM1L):c.1696G>T (p.Glu566Ter)	Pathogenic
3244417	NC_000012.11:g.(?32729292)(32875587_?)del	Pathogenic
3343933	NM_012062.5(DNM1L):c.1109T>C (p.Phe370Ser)	Pathogenic
3647817	NM_012062.5(DNM1L):c.1598dup (p.Ser534fs)	Pathogenic
3716101	NM_012062.5(DNM1L):c.322C>T (p.Arg108Ter)	Pathogenic
3729484	NM_012062.5(DNM1L):c.1503del (p.Phe501fs)	Pathogenic
3770240	NM_012062.5(DNM1L):c.223A>G (p.Lys75Glu)	Pathogenic
3897542	NM_001278464.2(DNM1L):c.270C>G (p.Asn90Lys)	Pathogenic
420713	NM_012062.5(DNM1L):c.1292G>A (p.Cys431Tyr)	Pathogenic
446169	NM_012062.5(DNM1L):c.5A>C (p.Glu2Ala)	Pathogenic
446170	NM_012062.5(DNM1L):c.575C>A (p.Ala192Glu)	Pathogenic
4722775	NM_012062.5(DNM1L):c.1824del (p.Lys608fs)	Pathogenic
4726534	NM_012062.5(DNM1L):c.499A>T (p.Arg167Ter)	Pathogenic
4798616	NM_012062.5(DNM1L):c.1979_1982del (p.Lys660fs)	Pathogenic
59805	GRCh38/hg38 12p11.21(chr12:32731855-32881857)x3	Pathogenic
6015	NM_012062.5(DNM1L):c.1184C>A (p.Ala395Asp)	Pathogenic
689730	NM_012062.5(DNM1L):c.763_764dup (p.Lys256fs)	Pathogenic
974819	NM_012062.5(DNM1L):c.115A>G (p.Ser39Gly)	Pathogenic
1066546	NM_012062.5(DNM1L):c.1099T>C (p.Cys367Arg)	Likely pathogenic

SpliceAI

4026 predictions. Top by Δscore:

Variant	Effect	Δscore
12:32679466:GT:G	donor_loss	1.0000
12:32679467:T:A	donor_loss	1.0000
12:32698312:A:T	donor_gain	1.0000
12:32701406:T:A	acceptor_gain	1.0000
12:32701411:TCA:T	acceptor_loss	1.0000
12:32701413:A:AG	acceptor_gain	1.0000
12:32701413:A:T	acceptor_loss	1.0000
12:32701414:G:GA	acceptor_gain	1.0000
12:32701414:GA:G	acceptor_gain	1.0000
12:32701414:GAGC:G	acceptor_gain	1.0000
12:32701414:GAGCA:G	acceptor_gain	1.0000
12:32701560:ATGG:A	donor_loss	1.0000
12:32701564:T:G	donor_loss	1.0000
12:32707361:TTCCA:T	acceptor_loss	1.0000
12:32707362:TCCA:T	acceptor_loss	1.0000
12:32707363:CCA:C	acceptor_loss	1.0000
12:32707364:CA:C	acceptor_loss	1.0000
12:32707365:A:AG	acceptor_gain	1.0000
12:32707365:A:AT	acceptor_loss	1.0000
12:32707365:AG:A	acceptor_gain	1.0000
12:32707365:AGG:A	acceptor_gain	1.0000
12:32707366:G:GG	acceptor_gain	1.0000
12:32707366:GG:G	acceptor_gain	1.0000
12:32707366:GGG:G	acceptor_gain	1.0000
12:32707411:AAG:A	donor_loss	1.0000
12:32707413:GGTA:G	donor_loss	1.0000
12:32707415:T:A	donor_loss	1.0000
12:32708141:A:AG	acceptor_gain	1.0000
12:32708142:A:G	acceptor_gain	1.0000
12:32708147:TTTTA:T	acceptor_loss	1.0000

AlphaMissense

4799 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:32679395:T:C	L11P	1.000
12:32679457:G:A	G32R	1.000
12:32679457:G:C	G32R	1.000
12:32679458:G:A	G32E	1.000
12:32679458:G:T	G32V	1.000
12:32701421:G:A	G37R	1.000
12:32701421:G:C	G37R	1.000
12:32701422:G:A	G37E	1.000
12:32701500:T:C	L63P	1.000
12:32707393:T:C	F93L	1.000
12:32707394:T:C	F93S	1.000
12:32707395:T:A	F93L	1.000
12:32707395:T:G	F93L	1.000
12:32710954:T:C	L132P	1.000
12:32710990:T:C	L144P	1.000
12:32710999:T:G	L147W	1.000
12:32711004:G:A	G149R	1.000
12:32711004:G:C	G149R	1.000
12:32713297:T:C	L182P	1.000
12:32713303:T:A	V184D	1.000
12:32713312:C:A	A187D	1.000
12:32713320:G:C	D190H	1.000
12:32713332:T:C	S194P	1.000
12:32718649:G:C	R209T	1.000
12:32718649:G:T	R209I	1.000
12:32718650:A:C	R209S	1.000
12:32718650:A:T	R209S	1.000
12:32718655:T:C	L211P	1.000
12:32718667:C:T	T215I	1.000
12:32718669:A:G	K216E	1.000

dbSNP variants (sampled 300 via entrez): RS1000026877 (12:32738043 A>G), RS1000095766 (12:32731289 C>A,G), RS1000096970 (12:32693971 A>G), RS1000137765 (12:32705056 T>A,C), RS1000164911 (12:32729644 G>C), RS1000273834 (12:32705276 T>C,G), RS1000277980 (12:32731733 G>A), RS1000297750 (12:32718208 C>A), RS1000333034 (12:32712022 G>C), RS1000391565 (12:32718081 A>C), RS1000418767 (12:32681603 C>A,T), RS1000476141 (12:32687879 T>C), RS1000551758 (12:32743316 T>C), RS1000562660 (12:32738506 C>T), RS1000590480 (12:32711399 C>A,T)

Disease associations

OMIM: gene MIM:603850 | disease phenotypes: MIM:614388, MIM:609040, MIM:610708, MIM:603563

GenCC curated gene-disease

Disease	Classification	Inheritance
encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1	Strong	Autosomal dominant
optic atrophy 5	Strong	Autosomal dominant
autosomal dominant optic atrophy, classic form	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (3)

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

Disease	Classification	Inheritance
Leigh syndrome	Limited	AR
encephalopathy due to mitochondrial and peroxisomal fission defect	Definitive	AD
Leigh syndrome	Limited	AD

Mondo (11): encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 (MONDO:0013726), arrhythmogenic right ventricular dysplasia 9 (MONDO:0012180), mitochondrial disease (MONDO:0044970), optic atrophy 5 (MONDO:0012543), hereditary ataxia (MONDO:0100309), encephalopathy due to mitochondrial and peroxisomal fission defect (MONDO:0054865), inherited retinal dystrophy (MONDO:0019118), Charcot-Marie-Tooth disease type 4 (MONDO:0018995), obesity disorder (MONDO:0011122), hereditary spastic paraplegia 8 (MONDO:0011339), autosomal dominant optic atrophy, classic form (MONDO:0008134)

Orphanet (10): DNM1L-related encephalopathy due to mitochondrial and peroxisomal fission defect (Orphanet:330050), Mitochondrial disease (Orphanet:68380), Autosomal dominant optic atrophy, classic form (Orphanet:98673), Hereditary ataxia (Orphanet:183518), Encephalopathy due to mitochondrial and peroxisomal fission defect (Orphanet:527276), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Charcot-Marie-Tooth disease type 4 (Orphanet:64749), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Autosomal dominant spastic paraplegia type 8 (Orphanet:100989), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

109 total (30 of 109 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000135	Hypogonadism
HP:0000252	Microcephaly
HP:0000307	Pointed chin
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000543	Optic disc pallor
HP:0000551	Color vision defect
HP:0000552	Tritanomaly
HP:0000602	Ophthalmoplegia
HP:0000603	Central scotoma
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000657	Oculomotor apraxia
HP:0000666	Horizontal nystagmus
HP:0000711	Restlessness
HP:0000726	Dementia
HP:0000738	Hallucinations
HP:0000819	Diabetes mellitus
HP:0000821	Hypothyroidism
HP:0001133	Constriction of peripheral visual field
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST90002395_122	Mean platelet volume	2.000000e-36
GCST90002401_236	Platelet distribution width	3.000000e-21
GCST90002402_369	Platelet count	3.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007984	platelet component distribution width
EFO:0004309	platelet count

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D058499	Retinal Dystrophies	C11.768.585.658
C563808	Arrhythmogenic Right Ventricular Dysplasia, Familial, 9 (supp.)
C531684	Hereditary spinal ataxia (supp.)
C537126	Optic atrophy 5 (supp.)
C580458	Spastic Paraplegia Type 8 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523118 (SINGLE PROTEIN)

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

ChEMBL bioactivities

86 potent at pChembl≥5 of 132 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.14	IC50	720	nM	CHEMBL4471636
6.04	IC50	910	nM	CHEMBL4467972
5.92	IC50	1200	nM	CHEMBL4454341
5.92	IC50	1200	nM	CHEMBL4554941
5.92	IC50	1200	nM	CHEMBL4437365
5.85	IC50	1400	nM	CHEMBL4472938
5.80	IC50	1600	nM	CHEMBL4464401
5.77	IC50	1700	nM	CHEMBL4557300
5.77	IC50	1700	nM	CHEMBL4472354
5.75	IC50	1800	nM	CHEMBL4517003
5.75	IC50	1800	nM	CHEMBL4466663
5.75	IC50	1800	nM	CHEMBL5799609
5.72	IC50	1900	nM	CHEMBL4452126
5.72	IC50	1900	nM	CHEMBL4514762
5.68	IC50	2100	nM	CHEMBL4452430
5.68	IC50	2100	nM	CHEMBL4527387
5.68	IC50	2100	nM	CHEMBL5862848
5.66	IC50	2200	nM	CHEMBL4514762
5.66	IC50	2200	nM	CHEMBL4549648
5.64	IC50	2300	nM	CHEMBL4448500
5.60	IC50	2500	nM	CHEMBL4446252
5.60	IC50	2500	nM	CHEMBL4560314
5.57	IC50	2700	nM	CHEMBL4435321
5.55	IC50	2800	nM	CHEMBL4571791
5.54	IC50	2900	nM	CHEMBL4456467
5.50	IC50	3200	nM	CHEMBL4573824
5.50	IC50	3200	nM	CHEMBL4545206
5.47	IC50	3400	nM	CHEMBL4556106
5.47	IC50	3400	nM	CHEMBL4466723
5.42	IC50	3800	nM	CHEMBL4526119
5.41	IC50	3900	nM	CHEMBL4437937
5.38	IC50	4200	nM	CHEMBL4468535
5.37	IC50	4300	nM	CHEMBL4440202
5.35	IC50	4500	nM	CHEMBL4445203
5.32	IC50	4800	nM	CHEMBL4545206
5.30	IC50	5000	nM	CHEMBL4458381
5.26	IC50	5500	nM	CHEMBL4539363
5.25	IC50	5600	nM	CHEMBL4483748
5.25	IC50	5600	nM	CHEMBL5830260
5.24	IC50	5700	nM	CHEMBL4585438
5.19	IC50	6400	nM	CHEMBL4442715
5.16	IC50	7000	nM	CHEMBL4555815
5.16	IC50	7000	nM	CHEMBL4514762
5.12	IC50	7600	nM	CHEMBL4549262
5.11	IC50	7800	nM	CHEMBL4465370
5.06	IC50	8700	nM	CHEMBL4585621
5.05	IC50	9000	nM	CHEMBL4457337
5.05	IC50	8900	nM	CHEMBL4476526
5.05	IC50	8900	nM	CHEMBL5986284
5.02	IC50	9600	nM	CHEMBL4584205

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Rotenone	increases expression, affects reaction, affects localization, decreases expression, increases phosphorylation (+1 more)	7
bisphenol A	decreases reaction, affects reaction, increases expression, affects localization, increases phosphorylation (+2 more)	4
3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone	affects reaction, increases expression, decreases reaction, affects localization, increases phosphorylation (+2 more)	4
Hydrogen Peroxide	affects reaction, decreases expression, decreases reaction, affects cotreatment, affects expression (+1 more)	4
Air Pollutants	affects cotreatment, decreases expression, increases abundance	3
Carbonyl Cyanide m-Chlorophenyl Hydrazone	increases reaction, affects cotreatment, affects phosphorylation, decreases expression, increases expression	3
Melatonin	affects cotreatment, decreases reaction, increases expression	3
1-Methyl-4-phenylpyridinium	increases expression, affects reaction, decreases reaction, increases reaction	3
bisphenol F	decreases reaction, increases expression, affects cotreatment, decreases phosphorylation	2
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	2
MitoTEMPO	decreases reaction, increases expression, increases phosphorylation	2
alpha-Chlorohydrin	affects localization, decreases reaction, increases expression, increases phosphorylation, affects reaction	2
Glucose	decreases reaction, increases expression, affects cotreatment	2
Dihydrotestosterone	affects phosphorylation, affects reaction, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Verapamil	affects localization, decreases reaction, increases phosphorylation	2
Cyclosporine	affects cotreatment, decreases phosphorylation, decreases reaction, increases phosphorylation, increases reaction (+1 more)	2
Oxidopamine	affects localization, decreases reaction, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
FR900359	decreases phosphorylation	1
dicrotophos	decreases expression	1
beta-N-methylamino-L-alanine	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
hydroxyhydroquinone	increases expression	1
mangiferin	decreases reaction, increases expression, increases phosphorylation	1
mono-(2-ethylhexyl)phthalate	affects cotreatment, affects phosphorylation	1
sulforaphane	increases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4418475	Binding	Inhibition of DRP1 (unknown origin) using GTP as substrate incubated for 20 mins by malachite green reagent based colorimetric assay	Dynamin-1-like protein inhibitors

Cellosaurus cell lines

2 cell lines: 1 induced pluripotent stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C1U8	LCHi003-A	Induced pluripotent stem cell	Male
CVCL_E1KP	HyCyte HeLa KO-hDNM1L	Cancer cell line	Female

Clinical trials (associated diseases)

106 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
NCT06461286	PHASE1	ACTIVE_NOT_RECRUITING	SAD of IVT PYC-001 in OPA1 Mutation-Associated Autosomal Dominant Optic Atrophy (Sundew)
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
NCT06970106	PHASE1/PHASE2	RECRUITING	Safety of Single and Repeat Dose of PYC-001 Eye Injections in People With Autosomal Dominant Optic Atrophy (Myrtle)
NCT06140329	Not specified	TERMINATED	Natural History of Autosomal Dominant Optic Atrophy (ADOA), Caused by OPA1 Mutation
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
NCT00786539	Not specified	COMPLETED	Mitochondria Inborn Errors of Metabolism and ANT Defects in Mitochondria Diseases
NCT00829270	Not specified	COMPLETED	Economic and Medical Evaluation of the Whole Mitochondrial DNA Screening by Surveyor and Mitochips Techniques