MFN2

Summary

MFN2 (mitofusin 2, HGNC:16877) is a protein-coding gene on chromosome 1p36.22, encoding Mitofusin-2 (O95140). Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion. It is a selective cancer dependency (DepMap: 76.8% of cell lines).

This gene encodes a mitochondrial membrane protein that participates in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network. This protein is involved in the regulation of vascular smooth muscle cell proliferation, and it may play a role in the pathophysiology of obesity. Mutations in this gene cause Charcot-Marie-Tooth disease type 2A2, and hereditary motor and sensory neuropathy VI, which are both disorders of the peripheral nervous system. Defects in this gene have also been associated with early-onset stroke. Two transcript variants encoding the same protein have been identified.

Source: NCBI Gene 9927 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple symmetric lipomatosis with partial lipodystrophy (Definitive, ClinGen) — +9 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 1,399 total — 101 pathogenic, 76 likely-pathogenic
• Phenotypes (HPO): 111
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 76.8% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_014874

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16877
Approved symbol	MFN2
Name	mitofusin 2
Location	1p36.22
Locus type	gene with protein product
Status	Approved
Aliases	CPRP1, KIAA0214, MARF, CMT2A2
Ensembl gene	ENSG00000116688
Ensembl biotype	protein_coding
OMIM	608507
Entrez	9927

Gene structure

Transcript identifiers

Ensembl transcripts: 79 — 63 protein_coding, 6 protein_coding_CDS_not_defined, 6 retained_intron, 4 nonsense_mediated_decay

ENST00000235329, ENST00000412236, ENST00000444836, ENST00000484391, ENST00000490079, ENST00000497302, ENST00000674548, ENST00000674658, ENST00000674706, ENST00000674817, ENST00000674910, ENST00000675043, ENST00000675053, ENST00000675113, ENST00000675194, ENST00000675231, ENST00000675298, ENST00000675374, ENST00000675404, ENST00000675483, ENST00000675512, ENST00000675528, ENST00000675530, ENST00000675781, ENST00000675817, ENST00000675872, ENST00000675919, ENST00000675959, ENST00000675987, ENST00000676293, ENST00000676295, ENST00000676369, ENST00000676426, ENST00000898883, ENST00000898884, ENST00000898885, ENST00000898886, ENST00000898887, ENST00000898888, ENST00000898889, ENST00000898890, ENST00000898891, ENST00000898892, ENST00000898893, ENST00000898894, ENST00000898895, ENST00000898896, ENST00000898897, ENST00000898898, ENST00000898899, ENST00000898900, ENST00000917332, ENST00000967393, ENST00000967394, ENST00000967395, ENST00000967396, ENST00000967397, ENST00000967398, ENST00000967399, ENST00000967400, ENST00000967401, ENST00000967402, ENST00000967403, ENST00000967404, ENST00000967405, ENST00000967406, ENST00000967407, ENST00000967408, ENST00000967409, ENST00000967410, ENST00000967411, ENST00000967412, ENST00000967413, ENST00000967414, ENST00000967415, ENST00000967416, ENST00000967417, ENST00000967418, ENST00000967419

RefSeq mRNA: 2 — MANE Select: NM_014874 NM_001127660, NM_014874

CCDS: CCDS30587

Canonical transcript exons

ENST00000235329 — 19 exons

Exon	Start	End
ENSE00001336968	11981970	11982114
ENSE00001336972	11980444	11980484
ENSE00001618211	12004509	12004613
ENSE00001654095	12004825	12004927
ENSE00001665725	11997297	11997421
ENSE00001674753	12001769	12001836
ENSE00001684279	12001401	12001554
ENSE00001684472	12007053	12007249
ENSE00001698937	11998988	11999095
ENSE00001702003	12006538	12006693
ENSE00001719147	11998770	11998878
ENSE00001770250	11996156	11996318
ENSE00001771463	12005711	12005931
ENSE00001777072	12001982	12002103
ENSE00001785284	12009592	12009726
ENSE00001785362	12003992	12004118
ENSE00001851384	12011496	12013508
ENSE00002228720	11992555	11992690
ENSE00003686591	11989165	11989343

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 99.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.4709 / max 330.0526, expressed in 1820 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
668	41.4417	1820
669	1.4100	802
667	0.4523	203
670	0.0742	23
673	0.0629	20
201354	0.0297	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.20	gold quality
heart left ventricle	UBERON:0002084	98.93	gold quality
cardiac ventricle	UBERON:0002082	98.89	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.63	gold quality
right atrium auricular region	UBERON:0006631	98.62	gold quality
cardiac atrium	UBERON:0002081	98.58	gold quality
gastrocnemius	UBERON:0001388	98.53	gold quality
muscle of leg	UBERON:0001383	98.38	gold quality
left ventricle myocardium	UBERON:0006566	98.20	gold quality
heart	UBERON:0000948	98.15	gold quality
muscle organ	UBERON:0001630	97.95	gold quality
skeletal muscle organ	UBERON:0014892	97.95	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.88	gold quality
lower esophagus	UBERON:0013473	97.80	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.80	gold quality
cranial nerve II	UBERON:0000941	97.66	gold quality
myocardium	UBERON:0002349	97.59	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.27	gold quality
diaphragm	UBERON:0001103	97.26	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.23	gold quality
skeletal muscle tissue	UBERON:0001134	97.21	gold quality
heart right ventricle	UBERON:0002080	97.19	gold quality
muscle tissue	UBERON:0002385	97.16	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.93	gold quality
body of tongue	UBERON:0011876	96.89	gold quality
skin of leg	UBERON:0001511	96.88	gold quality
vastus lateralis	UBERON:0001379	96.79	gold quality
esophagus	UBERON:0001043	96.75	gold quality
prefrontal cortex	UBERON:0000451	96.74	gold quality
quadriceps femoris	UBERON:0001377	96.67	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7303	no	1486.02
E-MTAB-2983	no	13.36
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESRRA, KLF4, PPARD, PPARG, PPARGC1A, SP1, STOML2, TP53

miRNA regulators (miRDB)

79 targeting MFN2, 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-4775	99.98	75.00	6394
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-4310	99.59	68.84	2527

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 76.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Results show that Fzo homologs mitofusin 1 and 2 are ubiquitous mitochondrial membrane proteins that interact with each other to facilitate mitochondrial targeting. (PMID:11950885)
• Drp1 and Mfn2, but not other proteins implicated in the regulation of mitochondrial morphology, colocalize with Bax in apoptotic foci (PMID:12499352)
• Mfn2-dependent mechanism of mitochondrial control is disturbed in obesity by reduced Mfn2 expression (PMID:12598526)
• Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A (PMID:15064763)
• Review. Mitofusin-2 stimulates mitochondrial substrate oxidation, respiration & membrane potential.It may play an important role in energy balance. Its expression is repressed in obese skeletal muscle suggesting a posible role in obesity. (PMID:15382611)
• Mfn2 triggers mitochondrial energization, at least in part, by regulating OXPHOS expression through signals that are independent of its role as a mitochondrial fusion protein (PMID:15829499)
• Mfn2 is a signaling GTPase regulating mitochondrial fusion; the nucleotide-dependent activation of Mfn2 concomitantly protects the organelle from permeability transition (PMID:15878861)
• Mfn1, Mfn2, NRF-2 and COX IV mRNA were increased 24 h post-exercise in skeletal muscle (PMID:15961417)
• Given the frequency of MFN2 mutations among CMT2 probands (3/13, or 23%), genetic testing of CMT2 patients should begin with a screen of the MFN2 gene. (PMID:16043786)
• HSG plays an essential role in mouse preimplantation development (PMID:16083859)
• Type 2 Charcot Marie Tooth Disease is genetically heterogeneous. It may or may not be caused by mutations in the MFN2 gene. (PMID:16087932)
• A study evaluating Mfn2 expression in skeletal muscle from obese or nonobese type 2 diabetic subjects in response to body weight, and the role of TNF-alpha and IL-6 in its regulation is reported. (PMID:16123358)
• the significant increase in mitofusin 2 mRNA levels may explain the increase in glucose oxidation observed in morbid obesity (PMID:16160866)
• This study identified a unique mutation in the gene mitofusin 2 (MFN2). In three families, the MFN2 mutation occurred de novo; in two families the mutation was subsequently transmitted from father to son indicating autosomal dominant inheritance. (PMID:16437557)
• A significant role of mutations in MFN2 in the pathogenesis of Charcot-Marie-Tooth disease type 2. (PMID:16762064)
• Charcot-Marie-Tooth disease-associated MFN2 mutant proteins induce abnormal clustering of small fragmented mitochondria in both neuronal cell bodies and proximal axons. Transport of these mitochondria in axons is significantly impaired. (PMID:17215403)
• findings suggest that mutations in the MFN2 gene are an important causative gene underlying Korean patients with Charcot-Marie-Tooth neuropathy type 2 (PMID:17309650)
• We also suggest that single patients with early-onset axonal polyneuropathies should be screened for MFN2 mutations. (PMID:17437620)
• a signaling role for Mfn2 in the regulation of apoptosis that extends beyond its role in mitochondrial fusion (PMID:17537722)
• Mitofusin-2 gene can inhibit the proliferation of MCF-7 cells and increase their chemosensitivity to camptothecin. (PMID:17697539)
• 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)
• Weight loss upregulates the peroxisome proliferator-activated receptor gamma coactivator gene, which in turn stimulates mitofusin-2 expression, which contributes to the improvement of insulin sensitivity. (PMID:17828388)
• MFN2 gene mutations were shown to be the most common cause of autosomal dominant hereditary axonopathy. In addition, MFN2 gene mutations were also identified in CMT type 6 (axonal neuropathy with optic nerve atrophy). (PMID:17874344)
• study reports a novel MFN2 mutation shared by two apparently unrelated Charcot-Marie-Tooth families originating from the same area in Southern Italy (PMID:17940179)
• observations are in agreement with the neuronal specificity of the disease and are consistent with a recent finding that mitochondrial fusion can be maintained in cells that express mutant Mfn2 protein due to complementation by a second mitofusin, Mfn1. (PMID:18316077)
• Cerebral involvement in axonal Charcot-Marie-Tooth neuropathy caused by mitofusin2 mutations. (PMID:18425620)
• Severe early-onset axonal neuropathy due to MFN2 mutations can present as an apparently recessively inherited neuropathy but the minimal phenotype in the parents suggests a semi-dominant mechanism. (PMID:18458227)
• mitofusin-2 may have a role in inhibiting the proliferation of MCF-7 cells and promoting their sensitivity to camptothecin with a synergic effect (PMID:18480994)
• early onset stroke without peripheral neuropathy caused by mutation in MFN2 (PMID:18490623)
• Cognitive impairment may be another feature of the MFN2-related phenotype. The widespread peripheral and CNS involvement, as well as the neurosensorial defects, underline the similarities among MFN2-related and primary mitochondrial disorders. (PMID:18946002)
• Neurophysiologic findings were most suggestive of axonal degeneration, but some onion bulbs were present in all mitofusin 2 mutations cases. Axonal mitochondria were smaller than normal, were round, and were abnormally aggregated. (PMID:18957892)
• A novel role of PGC-1beta in mitochondrial physiology, namely the control of mitochondrial fusion mainly through Mfn2. (PMID:18974884)
• mitofusin 2 tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial Ca(2+) uptake (PMID:19052620)
• IL-6 induces Bcl-2 expression to perform cytoprotective functions in response to oxygen toxicity, and that this effect is mediated by alterations in the interactions between Bak and Mfn1/Mfn2. Bcl-2 blocked the dissociation of Bak from Mfn2. (PMID:19168699)
• a role of mutant Mfn2 in neuronal function and physiopathology of Charcot-Marie-Tooth disease type 2A (Review) (PMID:19427854)
• MFN2 plays a role in controlling ATP/ADP exchanges in Charcot-Marie-Tooth type 2A disease (PMID:19618221)
• Data revealed that Mfn2 interacted with the carboxyl-terminal region of MAVS through a heptad repeat region, providing a structural perspective on the regulation of the mitochondrial antiviral response. (PMID:19690333)
• Results identify diverse effects of CMT2A mutations, including a possible role for Mfn2 ubiquitylation and degradation in CMT2A pathogenesis, and provide evidence for a link between Fzo1 GTP hydrolysis, ubiquitylation, and mitochondrial fusion. (PMID:19812251)
• Study found twenty-four Charcot-Marie-Tooth (CMT) disease patients from 14 different families were identified with nine different MFN2 mutations. (PMID:19889647)
• Mitofusin 2 mutations are a frequent cause of Charcot-Marie-Tooth disease type 2, with variable severity and either dominant or recessive inheritance. (PMID:20008656)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mfn2	ENSDARG00000079504
mus_musculus	Mfn2	ENSMUSG00000029020
rattus_norvegicus	Mfn2	ENSRNOG00000046424
drosophila_melanogaster	Marf	FBGN0029870
caenorhabditis_elegans		WBGENE00001509

Paralogs (1): MFN1 (ENSG00000171109)

Protein

Protein identifiers

Mitofusin-2 — O95140 (reviewed: O95140)

Alternative names: Transmembrane GTPase MFN2

All UniProt accessions (9): O95140, A0A6Q8PFJ4, A0A6Q8PFT5, A0A6Q8PGA3, A0A6Q8PGR2, A0A6Q8PGS9, A0A6Q8PGV8, A0A6Q8PH07, Q5JXC5

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion. Mitochondria are highly dynamic organelles, and their morphology is determined by the equilibrium between mitochondrial fusion and fission events. Overexpression induces the formation of mitochondrial networks. Membrane clustering requires GTPase activity and may involve a major rearrangement of the coiled coil domains. Plays a central role in mitochondrial metabolism and may be associated with obesity and/or apoptosis processes. Plays an important role in the regulation of vascular smooth muscle cell proliferation. Involved in the clearance of damaged mitochondria via selective autophagy (mitophagy). Is required for PRKN recruitment to dysfunctional mitochondria. Involved in the control of unfolded protein response (UPR) upon ER stress including activation of apoptosis and autophagy during ER stress. Acts as an upstream regulator of EIF2AK3 and suppresses EIF2AK3 activation under basal conditions.

Subunit / interactions. Forms homomultimers and heteromultimers with MFN1. Oligomerization is essential for mitochondrion fusion. Interacts with VAT1. Interacts with STOML2; may form heterooligomers. Interacts (phosphorylated) with PRKN. Interacts with EIF2AK3. Interacts with THG1L; THG1L probably functions as a guanyl-nucleotide exchange factor/GEF, activating MFN2. Interacts with TRABD.

Subcellular location. Mitochondrion outer membrane.

Tissue specificity. Ubiquitous; expressed at low level. Highly expressed in heart and kidney.

Post-translational modifications. Phosphorylated by PINK1. Ubiquitinated by non-degradative ubiquitin by PRKN, promoting mitochondrial fusion; deubiquitination by USP30 inhibits mitochondrial fusion. Ubiquitinated by HUWE1 when dietary stearate (C18:0) levels are low; ubiquitination inhibits mitochondrial fusion.

Disease relevance. Charcot-Marie-Tooth disease, axonal, type 2A2B (CMT2A2B) [MIM:617087] An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. CMT2A2B is a severe form with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry. Charcot-Marie-Tooth disease, axonal, type 2A2A (CMT2A2A) [MIM:609260] An autosomal dominant, axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. The disease is caused by variants affecting the gene represented in this entry. Neuropathy, hereditary motor and sensory, 6A, with optic atrophy (HMSN6A) [MIM:601152] An autosomal dominant neurologic disorder characterized by optic atrophy and peripheral sensorimotor neuropathy manifesting as axonal Charcot-Marie-Tooth disease. Charcot-Marie-Tooth disease is a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. It is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies and primary peripheral axonal neuropathies. Peripheral axonal neuropathies are characterized by signs of axonal regeneration in the absence of obvious myelin alterations, and normal or slightly reduced nerve conduction velocities. The disease is caused by variants affecting the gene represented in this entry. Lipomatosis, multiple symmetric, with or without peripheral neuropathy (MSL) [MIM:151800] An autosomal recessive disorder characterized by the growth of unencapsulated, lipomatous masses affecting the upper body, especially the cervical and thoracic regions. Lipomatosis can be disfiguring, and lipoma growth around the neck may cause difficulty swallowing or breathing. The age at onset ranges from childhood to young adulthood. Some patients develop distal muscle weakness and atrophy due to axonal peripheral neuropathy. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. A helix bundle is formed by helices from the N-terminal and the C-terminal part of the protein. The GTPase domain cannot be expressed by itself, without the helix bundle. Rearrangement of the helix bundle and/or of the coiled coil domains may bring membranes from adjacent mitochondria into close contact, and thereby play a role in mitochondrial fusion.

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

Isoforms (2)

UniProt ID	Names	Canonical?
O95140-1	1	yes
O95140-2	2

RefSeq proteins (2): NP_001121132, NP_055689* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006884	Fzo/mitofusin_HR2	Domain
IPR027094	Mitofusin_fam	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR030381	G_DYNAMIN_dom	Domain
IPR045063	Dynamin_N	Domain

Pfam: PF00350, PF04799

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (129 total): sequence variant 56, helix 17, mutagenesis site 15, strand 10, region of interest 8, turn 4, binding site 4, topological domain 3, splice variant 3, coiled-coil region 2, transmembrane region 2, modified residue 2, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6JFK	X-RAY DIFFRACTION	2
6JFM	X-RAY DIFFRACTION	2.09
6JFL	X-RAY DIFFRACTION	2.81

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95140-F1	81.94	0.44

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 (4): 106–111; 258–261; 305; 307

Post-translational modifications (2): 111, 442

Mutagenesis-validated functional residues (15):

Position	Phenotype
109	does not affect its ability to cluster mitochondria; when overexpressed.
110	does not affect its ability to cluster mitochondria; when overexpressed.
111	diminishes interaction with prkn in presence of pink1. abolishes phosphorylation by pink1 and interaction with prkn in p
111	interacts with prkn in absence of pink1; when associated with glu-442.
128	loss of function in promoting mitochondrial fusion.
230	loss of function in promoting mitochondrial fusion.
259	loss of function in promoting mitochondrial fusion.
259	does not affect its ability to cluster mitochondria; when overexpressed.
260	loss of function in promoting mitochondrial fusion.
266	loss of function in promoting mitochondrial fusion.
442	diminishes interaction with prkn in presence of pink1. abolishes phosphorylation by pink1 and interaction with prkn in p
442	interacts with prkn in absence of pink1; when associated with glu-111.
622–624	does not affect the targeting to mitochondrial outer membrane.
622–624	abolishes the targeting to mitochondrial outer membrane.
657–659	does not affect the targeting to mitochondrial outer membrane.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-5205685	PINK1-PRKN Mediated Mitophagy
R-HSA-9013419	RHOT2 GTPase cycle
R-HSA-983231	Factors involved in megakaryocyte development and platelet production
R-HSA-109582	Hemostasis
R-HSA-162582	Signal Transduction
R-HSA-1632852	Macroautophagy
R-HSA-5205647	Mitophagy
R-HSA-9612973	Autophagy
R-HSA-9663891	Selective autophagy
R-HSA-9715370	Miro GTPase Cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 448 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, GOBP_VACUOLE_ORGANIZATION, DITTMER_PTHLH_TARGETS_UP, GOBP_PROTEIN_TARGETING, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_BLASTOCYST_FORMATION, GOBP_MUSCLE_CELL_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_MACROAUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, MORF_RAF1, GOBP_ANIMAL_ORGAN_MORPHOGENESIS

GO Biological Process (18): blastocyst formation (GO:0001825), obsolete protein targeting to mitochondrion (GO:0006626), apoptotic process (GO:0006915), response to unfolded protein (GO:0006986), mitochondrial membrane organization (GO:0007006), mitochondrial fusion (GO:0008053), aerobic respiration (GO:0009060), protein localization to phagophore assembly site (GO:0034497), negative regulation of Ras protein signal transduction (GO:0046580), camera-type eye morphogenesis (GO:0048593), negative regulation of smooth muscle cell proliferation (GO:0048662), mitochondrion localization (GO:0051646), type 2 mitophagy (GO:0061734), positive regulation of cold-induced thermogenesis (GO:0120162), positive regulation of vascular associated smooth muscle cell proliferation (GO:1904707), positive regulation of vascular associated smooth muscle cell apoptotic process (GO:1905461), autophagy (GO:0006914), mitochondrion organization (GO:0007005)

GO Molecular Function (6): GTPase activity (GO:0003924), GTP binding (GO:0005525), ubiquitin protein ligase binding (GO:0031625), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), cytosol (GO:0005829), microtubule cytoskeleton (GO:0015630), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Mitophagy	1
Miro GTPase Cycle	1
Hemostasis	1
Autophagy	1
Selective autophagy	1
Macroautophagy	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion organization	2
cytoplasm	2
cellular anatomical structure	2
blastocyst development	1
anatomical structure formation involved in morphogenesis	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
response to topologically incorrect protein	1
mitochondrion	1
membrane organization	1
organelle fusion	1
cellular respiration	1
autophagosome assembly	1
intracellular protein localization	1
Ras protein signal transduction	1
regulation of Ras protein signal transduction	1
negative regulation of small GTPase mediated signal transduction	1
camera-type eye development	1
eye morphogenesis	1
negative regulation of cell population proliferation	1
smooth muscle cell proliferation	1
regulation of smooth muscle cell proliferation	1
organelle localization	1
mitophagy	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
positive regulation of smooth muscle cell proliferation	1
regulation of vascular associated smooth muscle cell proliferation	1
vascular associated smooth muscle cell proliferation	1
positive regulation of smooth muscle cell apoptotic process	1
vascular associated smooth muscle cell apoptotic process	1
regulation of vascular associated smooth muscle cell apoptotic process	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
organelle organization	1
ribonucleoside triphosphate phosphatase activity	1
guanyl ribonucleotide binding	1

Protein interactions and networks

STRING

3594 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MFN2	MARCHF5	Q9NX47	995
MFN2	PINK1	Q9BXM7	992
MFN2	FIS1	Q9Y3D6	986
MFN2	MFN1	Q8IWA4	983
MFN2	DNM1L	O00429	976
MFN2	RHOT1	Q8IXI2	964
MFN2	RHOT2	Q8IXI1	953
MFN2	BCL2L1	Q07817	953
MFN2	VDAC1	P21796	947
MFN2	BCL2	P10415	943
MFN2	PRKN	O60260	939
MFN2	HSPA9	P30036	937
MFN2	TRAK1	Q9UPV9	937
MFN2	PACS2	Q86VP3	936
MFN2	GDAP1	Q8TB36	923

IntAct

59 interactions, top by confidence:

A	B	Type	Score
MFN1	MFN2	psi-mi:“MI:0915”(physical association)	0.790
MFN1	MFN2	psi-mi:“MI:0914”(association)	0.790
MFN2	MFN1	psi-mi:“MI:0915”(physical association)	0.790
MARCHF5	MFN2	psi-mi:“MI:0914”(association)	0.670
MFN2	MARCHF5	psi-mi:“MI:0915”(physical association)	0.670
VSIG1	TTI1	psi-mi:“MI:0914”(association)	0.640
MFN2	PRKN	psi-mi:“MI:0915”(physical association)	0.580
BAK1	MFN2	psi-mi:“MI:0914”(association)	0.530
REEP5	SCAMP1	psi-mi:“MI:0914”(association)	0.530
GHITM	CCNB2	psi-mi:“MI:0914”(association)	0.530
VSIG1	TNPO2	psi-mi:“MI:0914”(association)	0.530
TRAK2	OGT	psi-mi:“MI:0914”(association)	0.530
GHITM	MFN2	psi-mi:“MI:0914”(association)	0.530
REEP5	PLSCR1	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
NCEH1	CLGN	psi-mi:“MI:0914”(association)	0.530
LRRK2	MFN2	psi-mi:“MI:0915”(physical association)	0.460
MFN2	LRRK2	psi-mi:“MI:0915”(physical association)	0.460
LRRK2	MFN2	psi-mi:“MI:0403”(colocalization)	0.460
SAMM50	MFN2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (200): MFN2 (Affinity Capture-RNA), MFN2 (Affinity Capture-MS), MFN2 (Affinity Capture-MS), HDAC6 (Affinity Capture-Western), MARCH5 (Affinity Capture-Western), SLC25A38 (Affinity Capture-Western), MFN2 (Affinity Capture-Western), MFN2 (Affinity Capture-Western), MFN2 (Affinity Capture-MS), MFN2 (Affinity Capture-MS), MFN2 (Affinity Capture-MS), MFN2 (Affinity Capture-MS), MFN2 (Affinity Capture-MS), MFN1 (Affinity Capture-Western), MFN2 (Affinity Capture-MS)

ESM2 similar proteins: A1E2I4, A2CI34, A7VK00, D3YWJ0, F1M649, O18412, O95140, P18588, P18589, P18590, P20591, P20592, P33237, Q1MT80, Q20CR4, Q23424, Q28379, Q3UP24, Q4ADG6, Q4ADG7, Q4ADG8, Q4TVR5, Q4VSN1, Q4VSN2, Q4VSN3, Q4VSN4, Q4VSN5, Q5R5G3, Q67E00, Q67E01, Q68CJ6, Q6NVF4, Q6P3V7, Q6Q899, Q6XUX0, Q6XUX1, Q6XUX2, Q6XUX3, Q6ZSC3, Q7YU24

Diamond homologs: O18412, O95140, Q7YU24, Q80U63, Q811U4, Q8IWA4, Q8R4Z9, Q8R500, Q9N6P4, Q23424

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
MAPK9	down-regulates	MFN2	phosphorylation
STOML2	“up-regulates quantity by expression”	MFN2	“transcriptional regulation”
PRKN	“down-regulates quantity”	MFN2	ubiquitination
HUWE1	“down-regulates quantity by destabilization”	MFN2	ubiquitination
MFN2	up-regulates	Mitochondrial_fusion
PINK1	“down-regulates quantity”	MFN2	ubiquitination
MAPK8	“down-regulates quantity”	MFN2	phosphorylation
PINK1	“down-regulates quantity”	MFN2	phosphorylation
MARCHF5	“up-regulates activity”	MFN2	ubiquitination
PKA	“up-regulates activity”	MFN2	phosphorylation
AMFR	“down-regulates quantity by destabilization”	MFN2	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

1399 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	101
Likely pathogenic	76
Uncertain significance	649
Likely benign	337
Benign	67

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1066607	NM_014874.4(MFN2):c.828G>T (p.Gln276His)	Pathogenic
1073982	NM_014874.4(MFN2):c.2054_2069+1171del	Pathogenic
1076044	NC_000001.10:g.(?12058817)(12059162_?)del	Pathogenic
1353202	NM_014874.4(MFN2):c.245del (p.Leu82fs)	Pathogenic
1367006	NM_014874.4(MFN2):c.382C>A (p.His128Asn)	Pathogenic
1401132	NM_014874.4(MFN2):c.1606del (p.Asp536fs)	Pathogenic
1451283	NM_014874.4(MFN2):c.1538_1541del (p.Ile513fs)	Pathogenic
1452732	NM_014874.4(MFN2):c.1789G>T (p.Glu597Ter)	Pathogenic
1453509	NM_014874.4(MFN2):c.475-7_478del	Pathogenic
1455514	NM_014874.4(MFN2):c.285G>T (p.Arg95Ser)	Pathogenic
1455961	NM_014874.4(MFN2):c.558dup (p.Lys187Ter)	Pathogenic
1458219	NM_014874.4(MFN2):c.1590_1591del (p.Cys530_Asp531delinsTer)	Pathogenic
1489614	NM_014874.4(MFN2):c.312-16_314del	Pathogenic
1525804	NM_014874.4(MFN2):c.1070A>C (p.Lys357Thr)	Pathogenic
1699942	NM_014874.4(MFN2):c.1069A>G (p.Lys357Glu)	Pathogenic
1703243	NM_014874.4(MFN2):c.600-31T>G	Pathogenic
1776421	NM_014874.4(MFN2):c.1612C>T (p.Gln538Ter)	Pathogenic
1962507	NM_014874.4(MFN2):c.505C>T (p.Gln169Ter)	Pathogenic
1998679	NM_014874.4(MFN2):c.1771C>T (p.Gln591Ter)	Pathogenic
2017340	NM_014874.4(MFN2):c.705G>C (p.Gln235His)	Pathogenic
2086764	NM_014874.4(MFN2):c.1156C>T (p.Gln386Ter)	Pathogenic
2088794	NM_014874.4(MFN2):c.1892G>A (p.Trp631Ter)	Pathogenic
2099187	NC_000001.11:g.12001772dup	Pathogenic
2114482	NM_014874.4(MFN2):c.2249_2250del (p.His750fs)	Pathogenic
216110	NM_014874.3(MFN2):c.600-?_816+?del	Pathogenic
217162	NM_014874.4(MFN2):c.2256C>A (p.Tyr752Ter)	Pathogenic
217164	NM_014874.4(MFN2):c.494A>G (p.His165Arg)	Pathogenic
2202704	NC_000001.11:g.12001772del	Pathogenic
2202705	NM_014874.4(MFN2):c.1100A>C (p.Gln367Pro)	Pathogenic
2268	NM_014874.4(MFN2):c.281G>A (p.Arg94Gln)	Pathogenic

SpliceAI

2945 predictions. Top by Δscore:

Variant	Effect	Δscore
1:11980300:GAGGC:G	donor_gain	1.0000
1:11980302:GGC:G	donor_gain	1.0000
1:11980303:GC:G	donor_gain	1.0000
1:11980303:GCG:G	donor_gain	1.0000
1:11989341:AAGGT:A	donor_loss	1.0000
1:11989342:AGG:A	donor_loss	1.0000
1:11989343:GGT:G	donor_loss	1.0000
1:11989344:G:GA	donor_loss	1.0000
1:11989345:T:G	donor_loss	1.0000
1:11992547:A:AG	acceptor_gain	1.0000
1:11992548:C:G	acceptor_gain	1.0000
1:11992553:A:AG	acceptor_gain	1.0000
1:11992554:G:GT	acceptor_gain	1.0000
1:11992554:GA:G	acceptor_gain	1.0000
1:11992554:GACAC:G	acceptor_gain	1.0000
1:11992686:GGCCG:G	donor_gain	1.0000
1:11992687:GCCG:G	donor_gain	1.0000
1:11992687:GCCGG:G	donor_gain	1.0000
1:11992689:CGG:C	donor_loss	1.0000
1:11992690:GGTAA:G	donor_loss	1.0000
1:11992691:G:A	donor_loss	1.0000
1:11992691:G:GG	donor_gain	1.0000
1:11992692:TAAGT:T	donor_loss	1.0000
1:11996150:TTCTA:T	acceptor_loss	1.0000
1:11996151:TCTA:T	acceptor_loss	1.0000
1:11996154:A:AG	acceptor_gain	1.0000
1:11996154:AG:A	acceptor_gain	1.0000
1:11996154:AGGAC:A	acceptor_gain	1.0000
1:11996155:G:GA	acceptor_gain	1.0000
1:11996155:GG:G	acceptor_gain	1.0000

AlphaMissense

5036 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:11989272:C:A	A35D	1.000
1:11996166:G:T	G108W	1.000
1:11996167:G:A	G108E	1.000
1:11996172:A:C	S110R	1.000
1:11996174:C:A	S110R	1.000
1:11996174:C:G	S110R	1.000
1:11996187:G:C	A115P	1.000
1:11996188:C:A	A115D	1.000
1:11998841:T:A	V224E	1.000
1:11998844:T:C	L225P	1.000
1:11999040:T:C	F254S	1.000
1:11999046:T:C	L256P	1.000
1:11999053:C:A	N258K	1.000
1:11999053:C:G	N258K	1.000
1:11999055:G:C	R259P	1.000
1:11999057:T:A	W260R	1.000
1:11999057:T:C	W260R	1.000
1:11999060:G:C	D261H	1.000
1:12001501:C:A	A306D	1.000
1:12001799:G:T	R334M	1.000
1:12001811:T:C	F338S	1.000
1:12002016:T:C	F358S	1.000
1:12005842:T:C	F543L	1.000
1:12005844:C:A	F543L	1.000
1:12005844:C:G	F543L	1.000
1:11989254:T:A	L29H	0.999
1:11989262:T:C	F32L	0.999
1:11989263:T:G	F32C	0.999
1:11989264:T:A	F32L	0.999
1:11989264:T:G	F32L	0.999

dbSNP variants (sampled 300 via entrez): RS1000027922 (1:12013498 G>C,T), RS1000166864 (1:12007744 G>A), RS1000183195 (1:12009060 C>A,G,T), RS1000302698 (1:12013799 A>G,T), RS1000446797 (1:12009388 G>A), RS1000484879 (1:12008917 A>G), RS1000498566 (1:12009200 G>C), RS1000514448 (1:12007992 C>G,T), RS1000672701 (1:12003669 A>T), RS1000682209 (1:12013091 G>A), RS1000818434 (1:12007762 TTTTC>T,TTTTCTTTC), RS1000848159 (1:11998009 G>A,C), RS1000921702 (1:11997872 A>T), RS1001105709 (1:11985255 G>A), RS1001169758 (1:12003406 T>A)

Disease associations

OMIM: gene MIM:608507 | disease phenotypes: MIM:609260, MIM:617087, MIM:601152, MIM:118220, MIM:151800, MIM:606482, MIM:609129, MIM:118210

GenCC curated gene-disease

Disease	Classification	Inheritance
axonal hereditary motor and sensory neuropathy	Definitive	Semidominant
Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;	Definitive	Autosomal recessive
neuropathy, hereditary motor and sensory, type 6A	Definitive	Autosomal dominant
Charcot-Marie-Tooth disease type 2A2	Strong	Autosomal dominant
hereditary motor and sensory neuropathy	Strong	Semidominant
multiple symmetric lipomatosis with partial lipodystrophy	Strong	Autosomal recessive
multiple symmetric lipomatosis	Supportive	Autosomal dominant
severe early-onset axonal neuropathy due to MFN2 deficiency	Supportive	Autosomal recessive
hereditary motor and sensory neuropathy type 6	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
multiple symmetric lipomatosis with partial lipodystrophy	Definitive	AR
obsolete axonal hereditary motor and sensory neuropathy	Definitive	SD

Mondo (27): Charcot-Marie-Tooth disease type 2 (MONDO:0018993), Charcot-Marie-Tooth disease type 2A2 (MONDO:0012231), cerebral palsy (MONDO:0006497), Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; (MONDO:0014906), hereditary motor and sensory neuropathy type 6 (MONDO:0019551), peripheral neuropathy (MONDO:0005244), neuropathy, hereditary motor and sensory, type 6A (MONDO:0011002), Charcot-Marie-Tooth disease (MONDO:0015626), severe early-onset axonal neuropathy due to MFN2 deficiency (MONDO:0019549), inherited retinal dystrophy (MONDO:0019118), optic atrophy (MONDO:0003608), cerebellar ataxia (MONDO:0000437), multiple symmetric lipomatosis (MONDO:0007908), axonal neuropathy (MONDO:0004183), microcephaly (MONDO:0001149)

Orphanet (17): Autosomal dominant Charcot-Marie-Tooth disease type 2 (Orphanet:64746), Autosomal dominant Charcot-Marie-Tooth disease type 2A2 (Orphanet:99947), Hereditary motor and sensory neuropathy type 6 (Orphanet:90120), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Severe early-onset axonal neuropathy due to MFN2 deficiency (Orphanet:90118), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Rare ataxia (Orphanet:102002), Multiple symmetric lipomatosis (Orphanet:2398), Hyperpigmentation of the skin (Orphanet:79375), Charcot-Marie-Tooth disease type 4 (Orphanet:64749), Autosomal dominant intermediate Charcot-Marie-Tooth disease type B (Orphanet:100044), Autosomal dominant Charcot-Marie-Tooth disease type 2M (Orphanet:228179), Multiple system atrophy, cerebellar type (Orphanet:227510), Genetic motor neuron disease (Orphanet:98505), Charcot-Marie-Tooth disease type 1 (Orphanet:65753)

HPO phenotypes

111 total (30 of 111 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000158	Macroglossia
HP:0000238	Hydrocephalus
HP:0000360	Tinnitus
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000458	Anosmia
HP:0000543	Optic disc pallor
HP:0000551	Color vision defect
HP:0000603	Central scotoma
HP:0000641	Dysmetric saccades
HP:0000648	Optic atrophy
HP:0000649	Abnormality of visual evoked potentials
HP:0000662	Nyctalopia
HP:0000855	Insulin resistance
HP:0001012	Multiple lipomas
HP:0001155	Abnormality of the hand
HP:0001257	Spasticity
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001276	Hypertonia
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001315	Reduced tendon reflexes
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001371	Flexion contracture
HP:0001387	Joint stiffness
HP:0001604	Vocal cord paresis

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001337_1	Platelet count	1.000000e-08
GCST002740_8	Inflammatory skin disease	1.000000e-06
GCST004923_1	Tuberculosis	1.000000e-11
GCST007578_3	Plasma homocysteine levels	7.000000e-09
GCST90002400_13	Plateletcrit	5.000000e-101
GCST90002402_528	Platelet count	2.000000e-67

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0004578	homocysteine measurement
EFO:0007985	platelet crit

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D002547	Cerebral Palsy	C10.228.140.140.254
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D015417	Hereditary Sensory and Motor Neuropathy	C10.500.300; C10.574.500.495; C10.668.829.800.300; C16.131.666.300; C16.320.400.375
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
C538268	Auditory neuropathy (supp.)
C563757	Charcot-Marie-Tooth Disease, Axonal, Type 2A2 (supp.)
C566138	Charcot-Marie-Tooth Disease, Axonal, Type 2a1 (supp.)
C531684	Hereditary spinal ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630807 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Mitofusin proteins

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 13B [PMID: 32506913]	Activation	8.11	pEC50

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.60	EC50	2.49	nM	CHEMBL4639460
8.42	EC50	3.8	nM	CHEMBL5088708

PubChem BioAssay actives

2 with measured affinity, of 7 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-[3-(5-cyclopropyl-4-phenyl-1,2,4-triazol-3-yl)propyl]-3-(2-methylcyclohexyl)urea	1812970: Activation of human Mitofusin-2 expressed in MEF cells assessed as enhancement of mitochondrial elongation and polarization measured after 48 hrs by Hoechst staining based confocal microscopy analysis	ec50	0.0025	uM
cis-(1R,2R)-N-(4-hydroxycyclohexyl)-2-(3-phenylpropyl)cyclopropane-1-carboxamide	1812970: Activation of human Mitofusin-2 expressed in MEF cells assessed as enhancement of mitochondrial elongation and polarization measured after 48 hrs by Hoechst staining based confocal microscopy analysis	ec50	0.0038	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Rotenone	increases expression, affects localization, decreases expression, decreases reaction	4
sodium arsenite	affects binding, increases reaction, affects reaction, decreases expression, increases expression	3
Acetylcysteine	decreases reaction, increases abundance, increases glutathionylation, affects cotreatment, increases degradation (+1 more)	3
Cadmium Chloride	increases abundance, decreases expression, decreases localization, increases degradation, decreases reaction (+4 more)	3
alpha-Chlorohydrin	decreases expression, decreases reaction	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Cadmium	decreases reaction, increases abundance, increases glutathionylation, decreases localization, increases expression (+4 more)	2
Carbonyl Cyanide m-Chlorophenyl Hydrazone	affects cotreatment, decreases reaction, increases degradation, affects localization, decreases expression (+1 more)	2
Doxorubicin	decreases expression	2
Fluorouracil	affects expression, increases expression	2
Particulate Matter	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
NMS-873	decreases expression, decreases reaction, increases abundance	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
nobiletin	decreases reaction, increases expression	1
sodium arsenate	decreases reaction, increases expression	1
o,p’-DDT	increases expression	1
mono-(2-ethylhexyl)phthalate	increases degradation, increases reaction, affects cotreatment, decreases reaction	1
fisetin	decreases expression, decreases reaction	1
cobaltous chloride	affects expression	1
salvin	decreases expression, decreases reaction	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	decreases methylation	1
acipimox	increases expression	1
polydatin	decreases reaction, increases expression	1
calpeptin	decreases reaction, increases degradation	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases reaction, increases abundance, decreases expression	1
amyloid beta-protein (1-42)	decreases expression, decreases reaction	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4618565	Binding	Activation of human MFN2 expressed in Mfn1 and Mfn2 double-null mouse MEF assessed as induction of open/active conformation at 5 uM incubated for 1 to 4 hrs by FRET assay	Discovery of 6-Phenylhexanamide Derivatives as Potent Stereoselective Mitofusin Activators for the Treatment of Mitochondrial Diseases. — J Med Chem

Cellosaurus cell lines

23 cell lines: 14 induced pluripotent stem cell, 4 cancer cell line, 4 embryonic stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A9XI	JUCTCi012-A	Induced pluripotent stem cell	Female
CVCL_A9XJ	JUCTCi012-B	Induced pluripotent stem cell	Female
CVCL_A9XK	JUCTCi012-C	Induced pluripotent stem cell	Female
CVCL_B1B7	Abcam HEK293 MFN2 KO	Transformed cell line	Female
CVCL_B7E9	NYSCF-AG0002-01-MR	Induced pluripotent stem cell	Male
CVCL_C0J2	JUCTCi019-A	Induced pluripotent stem cell	Male
CVCL_C0J3	JUCTCi019-B	Induced pluripotent stem cell	Male
CVCL_C0J4	JUCTCi019-C	Induced pluripotent stem cell	Male
CVCL_E2C4	HAP1 MFN2 (-) 2	Cancer cell line	Male
CVCL_E2C5	HAP1 MFN2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00154830	PHASE4	COMPLETED	Alterations of Functional Activities and Leg Stiffness After Hamstring Lengthening in Cerebral Palsy Children
NCT00432055	PHASE4	COMPLETED	Effects of Botulinum Toxin Type A in Adults With Cerebral Palsy
NCT00549471	PHASE4	TERMINATED	Improvement After Botulinum Toxin Injections to the Arms in Children With Cerebral Palsy
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NCT01603628	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Lower Limb Spasticity
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NCT01633736	PHASE3	UNKNOWN	Targeted Hip Strength Training in Children With Cerebral Palsy (CP)
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NCT02839785	PHASE3	TERMINATED	Analgesia and Physiotherapy in Children With Cerebral Palsy (ANTALKINECP)
NCT03110341	PHASE3	UNKNOWN	Effect of Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
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