Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFSP3FS)

• DOT Name: Mitochondrial dynamics protein MIEF1 (MIEF1)
• Synonyms: Mitochondrial dynamics protein of 51 kDa; Mitochondrial elongation factor 1; Smith-Magenis syndrome chromosomal region candidate gene 7 protein-like; SMCR7-like protein
• Gene Name: MIEF1
• Related Disease:
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Advanced cancer
  Carcinoma of liver and intrahepatic biliary tract
  Colorectal carcinoma
  Liver cancer
  Lung cancer
  Lung carcinoma
  Neoplasm
  Pulmonary arterial hypertension
  Recessive X-linked ichthyosis
• UniProt ID: MID51_HUMAN
• PDB ID: 4NXT; 4NXU; 4NXV; 4NXW; 4NXX; 5X9B; 5X9C
• Pfam ID: PF20266 ; PF21297
• Sequence:
  MAGAGERKGKKDDNGIGTAIDFVLSNARLVLGVGGAAMLGIATLAVKRMYDRAISAPTSP
  TRLSHSGKRSWEEPNWMGSPRLLNRDMKTGLSRSLQTLPTDSSTFDTDTFCPPRPKPVAR
  KGQVDLKKSRLRMSLQEKLLTYYRNRAAIPAGEQARAKQAAVDICAELRSFLRAKLPDMP
  LRDMYLSGSLYDDLQVVTADHIQLIVPLVLEQNLWSCIPGEDTIMNVPGFFLVRRENPEY
  FPRGSSYWDRCVVGGYLSPKTVADTFEKVVAGSINWPAIGSLLDYVIRPAPPPEALTLEV
  QYERDKHLFIDFLPSVTLGDTVLVAKPHRLAQYDNLWRLSLRPAETARLRALDQADSGCR
  SLCLKILKAICKSTPALGHLTASQLTNVILHLAQEEADWSPDMLADRFLQALRGLISYLE
  AGVLPSALNPKVNLFAELTPEEIDELGYTLYCSLSEPEVLLQT
• Function: Mitochondrial outer membrane protein which regulates mitochondrial fission. Promotes the recruitment and association of the fission mediator dynamin-related protein 1 (DNM1L) to the mitochondrial surface independently of the mitochondrial fission FIS1 and MFF proteins. Regulates DNM1L GTPase activity and DNM1L oligomerization. Binds ADP and can also bind GDP, although with lower affinity. Does not bind CDP, UDP, ATP, AMP or GTP. Inhibits DNM1L GTPase activity in the absence of bound ADP. Requires ADP to stimulate DNM1L GTPase activity and the assembly of DNM1L into long, oligomeric tubules with a spiral pattern, as opposed to the ring-like DNM1L oligomers observed in the absence of bound ADP. Does not require ADP for its function in recruiting DNM1L.
• Tissue Specificity: Expression is relatively high in heart, skeletal muscle, pancreas and kidney.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Thyroid cancer	DIS3VLDH	Definitive	Biomarker	[1]
Thyroid gland carcinoma	DISMNGZ0	Definitive	Biomarker	[1]
Thyroid tumor	DISLVKMD	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Liver cancer	DISDE4BI	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung carcinoma	DISTR26C	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Biomarker	[5]
Recessive X-linked ichthyosis	DISZY56W	moderate	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial dynamics protein MIEF1 (MIEF1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial dynamics protein MIEF1 (MIEF1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitochondrial dynamics protein MIEF1 (MIEF1).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Mitochondrial dynamics protein MIEF1 (MIEF1).	[10]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Mitochondrial dynamics protein MIEF1 (MIEF1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitochondrial dynamics protein MIEF1 (MIEF1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mitochondrial dynamics protein MIEF1 (MIEF1).	[12]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Mitochondrial dynamics protein MIEF1 (MIEF1).	[14]

References

• [1] Mst1 overexpression combined with Yap knockdown augments thyroid carcinoma apoptosis via promoting MIEF1-related mitochondrial fission and activating the JNK pathway.Cancer Cell Int. 2019 May 22;19:143. doi: 10.1186/s12935-019-0860-8. eCollection 2019.
• [2] Genetic ablation of TAZ induces HepG2 liver cancer cell apoptosis through activating the CaMKII/MIEF1 signaling pathway.Onco Targets Ther. 2019 Mar 1;12:1765-1779. doi: 10.2147/OTT.S196142. eCollection 2019.
• [3] Large tumor suppressor kinase 2 overexpression attenuates 5-FU-resistance in colorectal cancer via activating the JNK-MIEF1-mitochondrial division pathway.Cancer Cell Int. 2019 Apr 11;19:97. doi: 10.1186/s12935-019-0812-3. eCollection 2019.
• [4] Yap-Hippo promotes A549 lung cancer cell death via modulating MIEF1-related mitochondrial stress and activating JNK pathway.Biomed Pharmacother. 2019 May;113:108754. doi: 10.1016/j.biopha.2019.108754. Epub 2019 Mar 12.
• [5] Epigenetic Dysregulation of the Dynamin-Related Protein 1 Binding Partners MiD49 and MiD51 Increases Mitotic Mitochondrial Fission and Promotes Pulmonary Arterial Hypertension: Mechanistic and Therapeutic Implications.Circulation. 2018 Jul 17;138(3):287-304. doi: 10.1161/CIRCULATIONAHA.117.031258. Epub 2018 Feb 5.
• [6] Loss of MIEF1/MiD51 confers susceptibility to BAX-mediated cell death and PINK1-PRKN-dependent mitophagy.Autophagy. 2019 Dec;15(12):2107-2125. doi: 10.1080/15548627.2019.1596494. Epub 2019 Mar 28.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [12] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [13] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [14] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.