Details of Drug Off-Target (DOT)

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

• DOT Name: Mitochondrial fission factor (MFF)
• Gene Name: MFF
• Related Disease:
  Encephalopathy due to defective mitochondrial and peroxisomal fission 2
  Advanced cancer
  Alzheimer disease
  Autosomal dominant optic atrophy, classic form
  B-cell neoplasm
  Basal ganglia disorder
  Lung adenocarcinoma
  Mitochondrial disease
  Myelodysplastic syndrome
  Neoplasm
  Non-small-cell lung cancer
  Peripheral neuropathy
  Encephalopathy due to mitochondrial and peroxisomal fission defect
  Leigh syndrome
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Myocardial infarction
• UniProt ID: MFF_HUMAN
• Pfam ID: PF05644
• Sequence:
  MSKGTSSDTSLGRVSRAAFPSPTAAEMAEISRIQYEMEYTEGISQRMRVPEKLKVAPPNA
  DLEQGFQEGVPNASVIMQVPERIVVAGNNEDVSFSRPADLDLIQSTPFKPLALKTPPRVL
  TLSERPLDFLDLERPPTTPQNEEIRAVGRLKRERSMSENAVRQNGQLVRNDSLWHRSDSA
  PRNKISRFQAPISAPEYTVTPSPQQARVCPPHMLPEDGANLSSARGILSLIQSSTRRAYQ
  QILDVLDENRRPVLRGGSAAATSNPHHDNVRYGISNIDTTIEGTSDDLTVVDAASLRRQI
  IKLNRRLQLLEEENKERAKREMVMYSITVAFWLLNSWLWFRR
• Function: Plays a role in mitochondrial and peroxisomal fission. Promotes the recruitment and association of the fission mediator dynamin-related protein 1 (DNM1L) to the mitochondrial surface. May be involved in regulation of synaptic vesicle membrane dynamics by recruitment of DNM1L to clathrin-containing vesicles.
• Tissue Specificity: Highly expressed in heart, kidney, liver, brain, muscle, and stomach.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Encephalopathy due to defective mitochondrial and peroxisomal fission 2	DISXKTDN	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Autosomal dominant optic atrophy, classic form	DISXUAV9	Strong	Biomarker	[4]
B-cell neoplasm	DISVY326	Strong	Biomarker	[5]
Basal ganglia disorder	DIS2IRZ8	Strong	Genetic Variation	[1]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[2]
Mitochondrial disease	DISKAHA3	Strong	Genetic Variation	[6]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[2]
Peripheral neuropathy	DIS7KN5G	Strong	Biomarker	[1]
Encephalopathy due to mitochondrial and peroxisomal fission defect	DIS7RGZ4	Moderate	Autosomal recessive	[8]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[8]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[9]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[10]
Myocardial infarction	DIS655KI	Limited	Biomarker	[11]

11 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 Mitochondrial fission factor (MFF).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial fission factor (MFF).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial fission factor (MFF).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial fission factor (MFF).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitochondrial fission factor (MFF).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Mitochondrial fission factor (MFF).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Mitochondrial fission factor (MFF).	[18]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Mitochondrial fission factor (MFF).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitochondrial fission factor (MFF).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitochondrial fission factor (MFF).	[21]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Mitochondrial fission factor (MFF).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Mitochondrial fission factor (MFF).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Mitochondrial fission factor (MFF).	[20]
aconitine	DMFOZ60	Investigative	aconitine increases the phosphorylation of Mitochondrial fission factor (MFF).	[23]

References

• [1] Disturbed mitochondrial and peroxisomal dynamics due to loss of MFF causes Leigh-like encephalopathy, optic atrophy and peripheral neuropathy. J Med Genet. 2016 Apr;53(4):270-8. doi: 10.1136/jmedgenet-2015-103500. Epub 2016 Jan 18.
• [2] MFF Regulation of Mitochondrial Cell Death Is a Therapeutic Target in Cancer.Cancer Res. 2019 Dec 15;79(24):6215-6226. doi: 10.1158/0008-5472.CAN-19-1982. Epub 2019 Oct 3.
• [3] Neuronal susceptibility to beta-amyloid toxicity and ischemic injury involves histone deacetylase-2 regulation of endophilin-B1.Brain Pathol. 2019 Mar;29(2):164-175. doi: 10.1111/bpa.12647. Epub 2018 Oct 5.
• [4] Critical role of mitochondrial dysfunction and impaired mitophagy in diabetic nephropathy.J Cell Physiol. 2019 Nov;234(11):19223-19236. doi: 10.1002/jcp.28712. Epub 2019 Apr 29.
• [5] 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.
• [6] Clinical and Biochemical Features in a Patient With Mitochondrial Fission Factor Gene Alteration.Front Genet. 2018 Dec 7;9:625. doi: 10.3389/fgene.2018.00625. eCollection 2018.
• [7] Iron overload promotes mitochondrial fragmentation in mesenchymal stromal cells from myelodysplastic syndrome patients through activation of the AMPK/MFF/Drp1 pathway.Cell Death Dis. 2018 May 1;9(5):515. doi: 10.1038/s41419-018-0552-7.
• [8] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [9] Potential use of TIA-1, MFF, microRNA-200a-3p, and microRNA-27 as a novel marker for hepatocellular carcinoma.Biochem Biophys Res Commun. 2018 Mar 18;497(4):1117-1122. doi: 10.1016/j.bbrc.2018.02.189. Epub 2018 Feb 26.
• [10] Mitochondrial fission factor is a novel Myc-dependent regulator of mitochondrial permeability in cancer.EBioMedicine. 2019 Oct;48:353-363. doi: 10.1016/j.ebiom.2019.09.017. Epub 2019 Sep 18.
• [11] miR-761 regulates the mitochondrial network by targeting mitochondrial fission factor.Free Radic Biol Med. 2013 Dec;65:371-379. doi: 10.1016/j.freeradbiomed.2013.07.009. Epub 2013 Jul 15.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [17] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [18] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [19] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [22] 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.
• [23] 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.