Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8BDECJ)

• DOT Name: MICOS complex subunit MIC19 (CHCHD3)
• Synonyms: Coiled-coil-helix-coiled-coil-helix domain-containing protein 3
• Gene Name: CHCHD3
• Related Disease:
  Drug dependence
  Substance abuse
  Substance dependence
• UniProt ID: MIC19_HUMAN
• Pfam ID: PF05300
• Sequence:
  MGGTTSTRRVTFEADENENITVVKGIRLSENVIDRMKESSPSGSKSQRYSGAYGASVSDE
  ELKRRVAEELALEQAKKESEDQKRLKQAKELDRERAAANEQLTRAILRERICSEEERAKA
  KHLARQLEEKDRVLKKQDAFYKEQLARLEERSSEFYRVTTEQYQKAAEEVEAKFKRYESH
  PVCADLQAKILQCYRENTHQTLKCSALATQYMHCVNHAKQSMLEKGG
• Function: Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane. Has also been shown to function as a transcription factor which binds to the BAG1 promoter and represses BAG1 transcription. Plays an important role in the maintenance of the MICOS complex stability and the mitochondrial cristae morphology.
• Tissue Specificity: Detected at low levels in brain, placenta, lung, liver, kidney and pancreas with increased levels in heart and skeletal muscle. Higher expression in primary lung cancers than in normal lung tissue.
• Reactome Pathway:
  Cristae formation (R-HSA-8949613)
  Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Drug dependence	DIS9IXRC	Strong	Biomarker	[1]
Substance abuse	DIS327VW	Strong	Biomarker	[1]
Substance dependence	DISDRAAR	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of MICOS complex subunit MIC19 (CHCHD3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of MICOS complex subunit MIC19 (CHCHD3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of MICOS complex subunit MIC19 (CHCHD3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of MICOS complex subunit MIC19 (CHCHD3).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of MICOS complex subunit MIC19 (CHCHD3).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of MICOS complex subunit MIC19 (CHCHD3).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of MICOS complex subunit MIC19 (CHCHD3).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of MICOS complex subunit MIC19 (CHCHD3).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of MICOS complex subunit MIC19 (CHCHD3).	[10]
Okadaic acid	DM47CO1	Investigative	Okadaic acid decreases the expression of MICOS complex subunit MIC19 (CHCHD3).	[14]

3 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 MICOS complex subunit MIC19 (CHCHD3).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of MICOS complex subunit MIC19 (CHCHD3).	[12]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of MICOS complex subunit MIC19 (CHCHD3).	[13]

References

• [1] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] 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.
• [6] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [7] 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.
• [8] 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.
• [9] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [10] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Proteomic analysis reveals multiple patterns of response in cells exposed to a toxin mixture. Chem Res Toxicol. 2009 Jun;22(6):1077-85.