Details of Drug Off-Target (DOT)

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

• DOT Name: Mitofusin-1 (MFN1)
• Synonyms: EC 3.6.5.-; Fzo homolog; Transmembrane GTPase MFN1
• Gene Name: MFN1
• Related Disease:
  Acute kidney injury
  Adult respiratory distress syndrome
  Aortic valve stenosis
  B-cell neoplasm
  Carcinoma of esophagus
  Cardiac failure
  Charcot marie tooth disease
  Chronic renal failure
  Congestive heart failure
  End-stage renal disease
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Melanoma
  Migraine disorder
  Mitochondrial disease
  Myocardial ischemia
  Neoplasm
  Neoplasm of esophagus
  Neuromuscular disease
  Pulmonary fibrosis
  Pulmonary hypertension
  Rhinitis
  Amyotrophic lateral sclerosis
  Bone osteosarcoma
  Osteosarcoma
  Advanced cancer
  Autosomal dominant optic atrophy, classic form
  Hepatocellular carcinoma
  Prostate cancer
  Prostate carcinoma
  Status epilepticus seizure
• UniProt ID: MFN1_HUMAN
• PDB ID: 5GNR; 5GNS; 5GNT; 5GNU; 5GO4; 5GOE; 5GOF; 5GOM; 5YEW
• EC Number: 3.6.5.-
• Pfam ID: PF00350 ; PF04799
• Sequence:
  MAEPVSPLKHFVLAKKAITAIFDQLLEFVTEGSHFVEATYKNPELDRIATEDDLVEMQGY
  KDKLSIIGEVLSRRHMKVAFFGRTSSGKSSVINAMLWDKVLPSGIGHITNCFLSVEGTDG
  DKAYLMTEGSDEKKSVKTVNQLAHALHMDKDLKAGCLVRVFWPKAKCALLRDDLVLVDSP
  GTDVTTELDSWIDKFCLDADVFVLVANSESTLMNTEKHFFHKVNERLSKPNIFILNNRWD
  ASASEPEYMEDVRRQHMERCLHFLVEELKVVNALEAQNRIFFVSAKEVLSARKQKAQGMP
  ESGVALAEGFHARLQEFQNFEQIFEECISQSAVKTKFEQHTIRAKQILATVKNIMDSVNL
  AAEDKRHYSVEEREDQIDRLDFIRNQMNLLTLDVKKKIKEVTEEVANKVSCAMTDEICRL
  SVLVDEFCSEFHPNPDVLKIYKSELNKHIEDGMGRNLADRCTDEVNALVLQTQQEIIENL
  KPLLPAGIQDKLHTLIPCKKFDLSYNLNYHKLCSDFQEDIVFRFSLGWSSLVHRFLGPRN
  AQRVLLGLSEPIFQLPRSLASTPTAPTTPATPDNASQEELMITLVTGLASVTSRTSMGII
  IVGGVIWKTIGWKLLSVSLTMYGALYLYERLSWTTHAKERAFKQQFVNYATEKLRMIVSS
  TSANCSHQVKQQIATTFARLCQQVDITQKQLEEEIARLPKEIDQLEKIQNNSKLLRNKAV
  QLENELENFTKQFLPSSNEES
• Function: Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion. Membrane clustering requires GTPase activity. It may involve a major rearrangement of the coiled coil domains. 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 (in vitro). Has low GTPase activity.
• Tissue Specificity: Detected in kidney and heart (at protein level) . Ubiquitous . Expressed at slightly higher level in kidney and heart . Isoform 2 may be overexpressed in some tumors, such as lung cancers .
• 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

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute kidney injury	DISXZG0T	Definitive	Biomarker	[1]
Adult respiratory distress syndrome	DISIJV47	Strong	Therapeutic	[2]
Aortic valve stenosis	DISW7AQ9	Strong	Altered Expression	[3]
B-cell neoplasm	DISVY326	Strong	Biomarker	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[5]
Cardiac failure	DISDC067	Strong	Altered Expression	[6]
Charcot marie tooth disease	DIS3BT2L	Strong	Altered Expression	[7]
Chronic renal failure	DISGG7K6	Strong	Altered Expression	[8]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[6]
End-stage renal disease	DISXA7GG	Strong	Altered Expression	[8]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[5]
Melanoma	DIS1RRCY	Strong	Biomarker	[9]
Migraine disorder	DISFCQTG	Strong	Biomarker	[10]
Mitochondrial disease	DISKAHA3	Strong	Genetic Variation	[11]
Myocardial ischemia	DISFTVXF	Strong	Therapeutic	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[5]
Neuromuscular disease	DISQTIJZ	Strong	Biomarker	[14]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[15]
Pulmonary hypertension	DIS1RSP5	Strong	Biomarker	[16]
Rhinitis	DISKLMN7	Strong	Biomarker	[17]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Altered Expression	[18]
Bone osteosarcoma	DIST1004	moderate	Altered Expression	[19]
Osteosarcoma	DISLQ7E2	moderate	Altered Expression	[19]
Advanced cancer	DISAT1Z9	Disputed	Altered Expression	[20]
Autosomal dominant optic atrophy, classic form	DISXUAV9	Limited	Biomarker	[21]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[22]
Prostate cancer	DISF190Y	Limited	Biomarker	[23]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[23]
Status epilepticus seizure	DISY3BIC	Limited	Biomarker	[24]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Mitofusin-1 (MFN1) decreases the response to substance of Cisplatin.	[48]
Azide	DM5XZYB	Investigative	Mitofusin-1 (MFN1) decreases the response to substance of Azide.	[48]

23 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Mitofusin-1 (MFN1).	[25]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitofusin-1 (MFN1).	[26]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitofusin-1 (MFN1).	[27]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitofusin-1 (MFN1).	[28]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Mitofusin-1 (MFN1).	[29]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mitofusin-1 (MFN1).	[30]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Mitofusin-1 (MFN1).	[31]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Mitofusin-1 (MFN1).	[32]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Mitofusin-1 (MFN1).	[33]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Mitofusin-1 (MFN1).	[34]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Mitofusin-1 (MFN1).	[35]
Melatonin	DMKWFBT	Approved	Melatonin increases the expression of Mitofusin-1 (MFN1).	[36]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Mitofusin-1 (MFN1).	[37]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the expression of Mitofusin-1 (MFN1).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Mitofusin-1 (MFN1).	[39]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Mitofusin-1 (MFN1).	[40]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Mitofusin-1 (MFN1).	[41]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Mitofusin-1 (MFN1).	[43]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mitofusin-1 (MFN1).	[44]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Mitofusin-1 (MFN1).	[35]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Mitofusin-1 (MFN1).	[36]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos decreases the expression of Mitofusin-1 (MFN1).	[45]
aconitine	DMFOZ60	Investigative	aconitine decreases the expression of Mitofusin-1 (MFN1).	[47]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Mitofusin-1 (MFN1).	[42]
Octanal	DMTN0OK	Investigative	Octanal increases the methylation of Mitofusin-1 (MFN1).	[46]

References

• [1] Disrupted Renal Mitochondrial Homeostasis after Liver Transplantation in Rats.PLoS One. 2015 Oct 19;10(10):e0140906. doi: 10.1371/journal.pone.0140906. eCollection 2015.
• [2] Effect of Heme Oxygenase-1 on Mitofusin-1 protein in LPS-induced ALI/ARDS in rats.Sci Rep. 2016 Nov 10;6:36530. doi: 10.1038/srep36530.
• [3] Soluble ST2 promotes oxidative stress and inflammation in cardiac fibroblasts: an in vitro and in vivo study in aortic stenosis.Clin Sci (Lond). 2019 Jul 17;133(14):1537-1548. doi: 10.1042/CS20190475. Print 2019 Jul 31.
• [4] Arsenic-induced cardiotoxicity correlates with mitochondrial damage and trace elements imbalance in broiler chickens.Poult Sci. 2019 Feb 1;98(2):734-744. doi: 10.3382/ps/pey469.
• [5] Focally amplified lncRNA on chromosome 1 regulates apoptosis of esophageal cancer cells via DRP1 and mitochondrial dynamics.IUBMB Life. 2019 Feb;71(2):254-260. doi: 10.1002/iub.1971. Epub 2018 Nov 30.
• [6] Mitochondrial Dynamics in Tachycardiomyopathy.Cell Physiol Biochem. 2019;52(3):435-438. doi: 10.33594/000000031. Epub 2019 Mar 15.
• [7] Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration.J Neurosci. 2012 Mar 21;32(12):4145-55. doi: 10.1523/JNEUROSCI.6338-11.2012.
• [8] Reduction of mitochondria and up regulation of pyruvate dehydrogenase kinase 4 of skeletal muscle in patients with chronic kidney disease.Nephrology (Carlton). 2020 Mar;25(3):230-238. doi: 10.1111/nep.13606. Epub 2019 Jun 7.
• [9] Expression of mitochondrial dynamics markers during melanoma progression: Comparative study of head and neck cutaneous and mucosal melanomas.J Oral Pathol Med. 2019 May;48(5):373-381. doi: 10.1111/jop.12855. Epub 2019 Apr 10.
• [10] Abnormal mitochondrial dynamics and impaired mitochondrial biogenesis in trigeminal ganglion neurons in a rat model of migraine.Neurosci Lett. 2017 Jan 1;636:127-133. doi: 10.1016/j.neulet.2016.10.054. Epub 2016 Oct 29.
• [11] Gemini-Based Lipoplexes Complement the Mitochondrial Phenotype in MFN1-Knockout Mouse Embryonic Fibroblasts.Mol Pharm. 2019 Dec 2;16(12):4787-4796. doi: 10.1021/acs.molpharmaceut.9b00449. Epub 2019 Nov 5.
• [12] Vagal nerve stimulation improves mitochondrial dynamics via an M(3) receptor/CaMKK/AMPK pathway in isoproterenol-induced myocardial ischaemia.J Cell Mol Med. 2017 Jan;21(1):58-71. doi: 10.1111/jcmm.12938. Epub 2016 Aug 5.
• [13] Frameshift Mutations in Repeat Sequences of ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 Genes in Colon Cancers.Pathol Oncol Res. 2018 Jul;24(3):617-622. doi: 10.1007/s12253-017-0287-2. Epub 2017 Aug 12.
• [14] MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion.Nature. 2017 Feb 16;542(7641):372-376. doi: 10.1038/nature21077. Epub 2017 Jan 23.
• [15] Mitofusins regulate lipid metabolism to mediate the development of lung fibrosis.Nat Commun. 2019 Jul 29;10(1):3390. doi: 10.1038/s41467-019-11327-1.
• [16] MicroRNA-140 is elevated and mitofusin-1 is downregulated in the right ventricle of the Sugen5416/hypoxia/normoxia model of pulmonary arterial hypertension.Am J Physiol Heart Circ Physiol. 2016 Sep 1;311(3):H689-98. doi: 10.1152/ajpheart.00264.2016. Epub 2016 Jul 15.
• [17] PM(2.5)-Induced Oxidative Stress and Mitochondrial Damage in the Nasal Mucosa of Rats.Int J Environ Res Public Health. 2017 Jan 29;14(2):134. doi: 10.3390/ijerph14020134.
• [18] Disruption of skeletal muscle mitochondrial network genes and miRNAs in amyotrophic lateral sclerosis.Neurobiol Dis. 2013 Jan;49:107-17. doi: 10.1016/j.nbd.2012.08.015. Epub 2012 Sep 4.
• [19] MicroRNA-19b targets Mfn1 to inhibit Mfn1-induced apoptosis in osteosarcoma cells.Neoplasma. 2014;61(3):265-73. doi: 10.4149/neo_2014_034.
• [20] Mitochondrial dynamics regulates migration and invasion of breast cancer cells.Oncogene. 2013 Oct;32(40):4814-24. doi: 10.1038/onc.2012.494. Epub 2012 Nov 5.
• [21] Fluoride-induced renal dysfunction via respiratory chain complex abnormal expression and fusion elevation in mice.Chemosphere. 2020 Jan;238:124607. doi: 10.1016/j.chemosphere.2019.124607. Epub 2019 Aug 17.
• [22] MFN1-dependent alteration of mitochondrial dynamics drives hepatocellular carcinoma metastasis by glucose metabolic reprogramming.Br J Cancer. 2020 Jan;122(2):209-220. doi: 10.1038/s41416-019-0658-4. Epub 2019 Dec 10.
• [23] Mitofusin 1 degradation is induced by a disruptor of mitochondrial calcium homeostasis, CGP37157: a role in apoptosis in prostate cancer cells.Int J Oncol. 2014 May;44(5):1767-73. doi: 10.3892/ijo.2014.2343. Epub 2014 Mar 13.
• [24] Status epilepticus triggers early mitochondrial fusion in the rat hippocampus in a lithium-pilocarpine model.Epilepsy Res. 2016 Jul;123:11-9. doi: 10.1016/j.eplepsyres.2016.03.007. Epub 2016 Mar 29.
• [25] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [26] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [27] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [28] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [29] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [30] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [31] Tea polyphenols ameliorates neural redox imbalance and mitochondrial dysfunction via mechanisms linking the key circadian regular Bmal1. Food Chem Toxicol. 2017 Dec;110:189-199. doi: 10.1016/j.fct.2017.10.031. Epub 2017 Oct 20.
• [32] 5-Fluorouracil inhibits neural differentiation via Mfn1/2 reduction in human induced pluripotent stem cells. J Toxicol Sci. 2018;43(12):727-734. doi: 10.2131/jts.43.727.
• [33] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [34] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [35] Protective effects of silibinin against ethanol- or acetaldehyde-caused damage in liver cell lines involve the repression of mitochondrial fission. Toxicol In Vitro. 2022 Apr;80:105330. doi: 10.1016/j.tiv.2022.105330. Epub 2022 Feb 11.
• [36] Melatonin prevents blood-retinal barrier breakdown and mitochondrial dysfunction in high glucose and hypoxia-induced in vitro diabetic macular edema model. Toxicol In Vitro. 2021 Sep;75:105191. doi: 10.1016/j.tiv.2021.105191. Epub 2021 May 5.
• [37] Disruption of adaptive energy metabolism and elevated ribosomal p-S6K1 levels contribute to INCL pathogenesis: partial rescue by resveratrol. Hum Mol Genet. 2011 Mar 15;20(6):1111-21. doi: 10.1093/hmg/ddq555. Epub 2010 Dec 28.
• [38] Synthetic oleanane triterpenoid derivative CDDO-Me disrupts cellular bioenergetics to suppress pancreatic ductal adenocarcinoma via targeting SLC1A5. J Biochem Mol Toxicol. 2022 Nov;36(11):e23192. doi: 10.1002/jbt.23192. Epub 2022 Aug 5.
• [39] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [40] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [41] Lon protease: a novel mitochondrial matrix protein in the interconnection between drug-induced mitochondrial dysfunction and endoplasmic reticulum stress. Br J Pharmacol. 2017 Dec;174(23):4409-4429. doi: 10.1111/bph.14045. Epub 2017 Nov 7.
• [42] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [43] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [44] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [45] Chlorpyrifos inhibits neural induction via Mfn1-mediated mitochondrial dysfunction in human induced pluripotent stem cells. Sci Rep. 2017 Jan 23;7:40925. doi: 10.1038/srep40925.
• [46] DNA Methylome Analysis of Saturated Aliphatic Aldehydes in Pulmonary Toxicity. Sci Rep. 2018 Jul 12;8(1):10497. doi: 10.1038/s41598-018-28813-z.
• [47] Aconitine induces mitochondrial energy metabolism dysfunction through inhibition of AMPK signaling and interference with mitochondrial dynamics in SH-SY5Y cells. Toxicol Lett. 2021 Sep 1;347:36-44. doi: 10.1016/j.toxlet.2021.04.020. Epub 2021 May 1.
• [48] Fragmented mitochondria are sensitized to Bax insertion and activation during apoptosis. Am J Physiol Cell Physiol. 2011 Mar;300(3):C447-55. doi: 10.1152/ajpcell.00402.2010. Epub 2010 Dec 15.