Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPYN8A3)

DOT Name	Mitofusin-2 (MFN2)
Synonyms	EC 3.6.5.-; Transmembrane GTPase MFN2
Gene Name	MFN2
Related Disease	Advanced cancer ( ) Obsolete axonal hereditary motor and sensory neuropathy ( ) Peripheral neuropathy ( ) Autosomal dominant optic atrophy ( ) B-cell neoplasm ( ) Bladder cancer ( ) Carcinoma of liver and intrahepatic biliary tract ( ) Cardiac failure ( ) Cervical carcinoma ( ) Charcot-Marie-Tooth disease type 2A2 ( ) Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; ( ) Congestive heart failure ( ) Diabetic kidney disease ( ) Diabetic retinopathy ( ) Essential hypertension ( ) Hereditary motor and sensory neuropathy ( ) High blood pressure ( ) Liver cancer ( ) Melanoma ( ) Mitochondrial disease ( ) Myocardial ischemia ( ) Nervous system disease ( ) Neuroblastoma ( ) Non-insulin dependent diabetes ( ) Parkinson disease ( ) Prediabetes syndrome ( ) Pulmonary fibrosis ( ) Stroke ( ) Tuberculosis ( ) Alzheimer disease ( ) Axonal neuropathy ( ) Gastric cancer ( ) Lung adenocarcinoma ( ) Obesity ( ) Stomach cancer ( ) Hereditary motor and sensory neuropathy type 6 ( ) Multiple symmetric lipomatosis ( ) Severe early-onset axonal neuropathy due to MFN2 deficiency ( ) Atopic dermatitis ( ) Breast cancer ( ) Breast carcinoma ( ) Carotid stenosis ( ) Charcot-Marie-Tooth disease type 2 ( ) Myocardial infarction ( ) Pancreatic cancer ( ) Restless legs syndrome ( )
UniProt ID	MFN2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	6JFK; 6JFL; 6JFM
EC Number	3.6.5.-
Pfam ID	PF00350 ; PF04799
Sequence	MSLLFSRCNSIVTVKKNKRHMAEVNASPLKHFVTAKKKINGIFEQLGAYIQESATFLEDT YRNAELDPVTTEEQVLDVKGYLSKVRGISEVLARRHMKVAFFGRTSNGKSTVINAMLWDK VLPSGIGHTTNCFLRVEGTDGHEAFLLTEGSEEKRSAKTVNQLAHALHQDKQLHAGSLVS VMWPNSKCPLLKDDLVLMDSPGIDVTTELDSWIDKFCLDADVFVLVANSESTLMQTEKHF FHKVSERLSRPNIFILNNRWDASASEPEYMEEVRRQHMERCTSFLVDELGVVDRSQAGDR IFFVSAKEVLNARIQKAQGMPEGGGALAEGFQVRMFEFQNFERRFEECISQSAVKTKFEQ HTVRAKQIAEAVRLIMDSLHMAAREQQVYCEEMREERQDRLKFIDKQLELLAQDYKLRIK QITEEVERQVSTAMAEEIRRLSVLVDDYQMDFHPSPVVLKVYKNELHRHIEEGLGRNMSD RCSTAITNSLQTMQQDMIDGLKPLLPVSVRSQIDMLVPRQCFSLNYDLNCDKLCADFQED IEFHFSLGWTMLVNRFLGPKNSRRALMGYNDQVQRPIPLTPANPSMPPLPQGSLTQEEFM VSMVTGLASLTSRTSMGILVVGGVVWKAVGWRLIALSFGLYGLLYVYERLTWTTKAKERA FKRQFVEHASEKLQLVISYTGSNCSHQVQQELSGTFAHLCQQVDVTRENLEQEIAAMNKK IEVLDSLQSKAKLLRNKAGWLDSELNMFTHQYLQPSR
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 (Probable). 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.
Tissue Specificity	Ubiquitous; expressed at low level. Highly expressed in heart and kidney.
KEGG Pathway	Mitophagy - animal (hsa04137 ) NOD-like receptor sig.ling pathway (hsa04621 ) Parkinson disease (hsa05012 ) Pathways of neurodegeneration - multiple diseases (hsa05022 )
Reactome Pathway	RHOT2 GTPase cycle (R-HSA-9013419 ) Factors involved in megakaryocyte development and platelet production (R-HSA-983231 ) PINK1-PRKN Mediated Mitophagy (R-HSA-5205685 )

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Obsolete axonal hereditary motor and sensory neuropathy	DISXSTX1	Definitive	Semidominant	[2]
Peripheral neuropathy	DIS7KN5G	Definitive	Genetic Variation	[3]
Autosomal dominant optic atrophy	DISOCR1N	Strong	Genetic Variation	[4]
B-cell neoplasm	DISVY326	Strong	Biomarker	[5]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[6]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[7]
Cardiac failure	DISDC067	Strong	Altered Expression	[8]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[9]
Charcot-Marie-Tooth disease type 2A2	DIS8WD1Q	Strong	Autosomal dominant	[10]
Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;	DISGXQJM	Strong	Autosomal recessive	[11]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[8]
Diabetic kidney disease	DISJMWEY	Strong	Therapeutic	[12]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[13]
Essential hypertension	DIS7WI98	Strong	Posttranslational Modification	[14]
Hereditary motor and sensory neuropathy	DISR0X2K	Strong	Genetic Variation	[15]
High blood pressure	DISY2OHH	Strong	Biomarker	[16]
Liver cancer	DISDE4BI	Strong	Biomarker	[7]
Melanoma	DIS1RRCY	Strong	Biomarker	[17]
Mitochondrial disease	DISKAHA3	Strong	Genetic Variation	[18]
Myocardial ischemia	DISFTVXF	Strong	Altered Expression	[19]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[20]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[21]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[22]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[23]
Prediabetes syndrome	DISH2I53	Strong	Biomarker	[24]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[25]
Stroke	DISX6UHX	Strong	Genetic Variation	[26]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[27]
Alzheimer disease	DISF8S70	moderate	Altered Expression	[28]
Axonal neuropathy	DIS5S2BC	moderate	Genetic Variation	[29]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[30]
Lung adenocarcinoma	DISD51WR	moderate	Biomarker	[31]
Obesity	DIS47Y1K	moderate	Biomarker	[32]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[30]
Hereditary motor and sensory neuropathy type 6	DIS27OAR	Supportive	Autosomal dominant	[33]
Multiple symmetric lipomatosis	DIS22LMD	Supportive	Autosomal dominant	[34]
Severe early-onset axonal neuropathy due to MFN2 deficiency	DISIYHFA	Supportive	Autosomal recessive	[35]
Atopic dermatitis	DISTCP41	Limited	Genetic Variation	[36]
Breast cancer	DIS7DPX1	Limited	Biomarker	[37]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[37]
Carotid stenosis	DISZA8D0	Limited	Therapeutic	[38]
Charcot-Marie-Tooth disease type 2	DISR30O9	Limited	Genetic Variation	[3]
Myocardial infarction	DIS655KI	Limited	Therapeutic	[39]
Pancreatic cancer	DISJC981	Limited	Biomarker	[40]
Restless legs syndrome	DISNWY00	Limited	Biomarker	[41]
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⏷ Show the Full List of 46 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Azide	DM5XZYB	Investigative	Mitofusin-2 (MFN2) decreases the response to substance of Azide.	[58]
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16 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Mitofusin-2 (MFN2).	[42]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mitofusin-2 (MFN2).	[44]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitofusin-2 (MFN2).	[45]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitofusin-2 (MFN2).	[46]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitofusin-2 (MFN2).	[47]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Mitofusin-2 (MFN2).	[48]
Melatonin	DMKWFBT	Approved	Melatonin increases the expression of Mitofusin-2 (MFN2).	[49]
Efavirenz	DMC0GSJ	Approved	Efavirenz increases the expression of Mitofusin-2 (MFN2).	[50]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Mitofusin-2 (MFN2).	[51]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Mitofusin-2 (MFN2).	[52]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the expression of Mitofusin-2 (MFN2).	[53]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Mitofusin-2 (MFN2).	[52]
CERC-801	DM3SZ7P	Phase 2	CERC-801 increases the expression of Mitofusin-2 (MFN2).	[54]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Mitofusin-2 (MFN2).	[50]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitofusin-2 (MFN2).	[56]
AM251	DMTAWHL	Investigative	AM251 decreases the expression of Mitofusin-2 (MFN2).	[57]
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⏷ Show the Full List of 16 Drug(s)

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Mitofusin-2 (MFN2).	[43]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Mitofusin-2 (MFN2).	[55]
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References

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32	Mfn2 deletion in brown adipose tissue protects from insulin resistance and impairs thermogenesis.EMBO Rep. 2017 Jul;18(7):1123-1138. doi: 10.15252/embr.201643827. Epub 2017 May 24.
33	Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol. 2006 Feb;59(2):276-81. doi: 10.1002/ana.20797.
34	Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy. Hum Mol Genet. 2015 Sep 15;24(18):5109-14. doi: 10.1093/hmg/ddv229. Epub 2015 Jun 17.
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