Details of Drug Off-Target (DOT)

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

• DOT Name: Dynamin-like 120 kDa protein, mitochondrial (OPA1)
• Synonyms: EC 3.6.5.5; Optic atrophy protein 1
• Gene Name: OPA1
• Related Disease:
  Autosomal dominant optic atrophy, classic form
  OPA1-related optic atrophy with or without extraocular features
  Behr syndrome
  Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type)
  Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy
  Leigh syndrome
  Autosomal dominant optic atrophy plus syndrome
• UniProt ID: OPA1_HUMAN
• PDB ID: 6JTG; 8CT1; 8CT9; 8EEW; 8EF7; 8EFF; 8EFR; 8EFS; 8EFT
• EC Number: 3.6.5.5
• Pfam ID: PF00350 ; PF19434
• Sequence:
  MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSHHPTLKLQRPQLRTSFQ
  QFSSLTNLPLRKLKFSPIKYGYQPRRNFWPARLATRLLKLRYLILGSAVGGGYTAKKTFD
  QWKDMIPDLSEYKWIVPDIVWEIDEYIDFEKIRKALPSSEDLVKLAPDFDKIVESLSLLK
  DFFTSGSPEETAFRATDRGSESDKHFRKVSDKEKIDQLQEELLHTQLKYQRILERLEKEN
  KELRKLVLQKDDKGIHHRKLKKSLIDMYSEVLDVLSDYDASYNTQDHLPRVVVVGDQSAG
  KTSVLEMIAQARIFPRGSGEMMTRSPVKVTLSEGPHHVALFKDSSREFDLTKEEDLAALR
  HEIELRMRKNVKEGCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSGMAPDTKETIFS
  ISKAYMQNPNAIILCIQDGSVDAERSIVTDLVSQMDPHGRRTIFVLTKVDLAEKNVASPS
  RIQQIIEGKLFPMKALGYFAVVTGKGNSSESIEAIREYEEEFFQNSKLLKTSMLKAHQVT
  TRNLSLAVSDCFWKMVRESVEQQADSFKATRFNLETEWKNNYPRLRELDRNELFEKAKNE
  ILDEVISLSQVTPKHWEEILQQSLWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQW
  TDKQLPNKAVEVAWETLQEEFSRFMTEPKGKEHDDIFDKLKEAVKEESIKRHKWNDFAED
  SLRVIQHNALEDRSISDKQQWDAAIYFMEEALQARLKDTENAIENMVGPDWKKRWLYWKN
  RTQEQCVHNETKNELEKMLKCNEEHPAYLASDEITTVRKNLESRGVEVDPSLIKDTWHQV
  YRRHFLKTALNHCNLCRRGFYYYQRHFVDSELECNDVVLFWRIQRMLAITANTLRQQLTN
  TEVRRLEKNVKEVLEDFAEDGEKKIKLLTGKRVQLAEDLKKVREIQEKLDAFIEALHQEK
• Function: Dynamin-related GTPase that is essential for normal mitochondrial morphology by regulating the equilibrium between mitochondrial fusion and mitochondrial fission. Coexpression of isoform 1 with shorter alternative products is required for optimal activity in promoting mitochondrial fusion. Binds lipid membranes enriched in negatively charged phospholipids, such as cardiolipin, and promotes membrane tubulation. The intrinsic GTPase activity is low, and is strongly increased by interaction with lipid membranes. Plays a role in remodeling cristae and the release of cytochrome c during apoptosis. Proteolytic processing in response to intrinsic apoptotic signals may lead to disassembly of OPA1 oligomers and release of the caspase activator cytochrome C (CYCS) into the mitochondrial intermembrane space. Plays a role in mitochondrial genome maintenance ; [Dynamin-like 120 kDa protein, form S1]: Inactive form produced by cleavage at S1 position by OMA1 following stress conditions that induce loss of mitochondrial membrane potential, leading to negative regulation of mitochondrial fusion; [Isoform 4]: Isoforms that contain the alternative exon 4b are required for mitochondrial genome maintenance, possibly by anchoring the mitochondrial nucleoids to the inner mitochondrial membrane; [Isoform 5]: Isoforms that contain the alternative exon 4b are required for mitochondrial genome maintenance, possibly by anchoring the mitochondrial nucleoids to the inner mitochondrial membrane.
• Tissue Specificity: Highly expressed in retina. Also expressed in brain, testis, heart and skeletal muscle. Isoform 1 expressed in retina, skeletal muscle, heart, lung, ovary, colon, thyroid gland, leukocytes and fetal brain. Isoform 2 expressed in colon, liver, kidney, thyroid gland and leukocytes. Low levels of all isoforms expressed in a variety of tissues.
• KEGG Pathway:
  Mitophagy - animal (hsa04137)
  Spinocerebellar ataxia (hsa05017)
• Reactome Pathway: Regulation of Apoptosis (R-HSA-169911)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant optic atrophy, classic form	DISXUAV9	Definitive	Autosomal dominant	[1]
OPA1-related optic atrophy with or without extraocular features	DISXL1WB	Definitive	Semidominant	[2]
Behr syndrome	DIS0X9PZ	Strong	Autosomal recessive	[3]
Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type)	DIS1WWEQ	Strong	Autosomal recessive	[1]
Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy	DISBN7PA	Strong	Autosomal dominant	[4]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[2]
Autosomal dominant optic atrophy plus syndrome	DISE9P9R	Supportive	Autosomal dominant	[5]

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 Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[11]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[12]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[13]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[14]
Efavirenz	DMC0GSJ	Approved	Efavirenz increases the expression of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[21]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[13]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[22]
aconitine	DMFOZ60	Investigative	aconitine decreases the expression of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[23]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl increases the cleavage of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[17]

3 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 affects the methylation of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[18]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Dynamin-like 120 kDa protein, mitochondrial (OPA1).	[20]

References

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• [9] Tea polyphenols direct Bmal1-driven ameliorating of the redox imbalance and mitochondrial dysfunction in hepatocytes. Food Chem Toxicol. 2018 Dec;122:181-193.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [13] 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.
• [14] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [15] 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.
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• [18] 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.
• [19] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [20] 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.
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• [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.