Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA6IVKQ)

• DOT Name: FUN14 domain-containing protein 1 (FUNDC1)
• Gene Name: FUNDC1
• Related Disease:
  Type-1/2 diabetes
  Carcinoma of liver and intrahepatic biliary tract
  Cardiac failure
  Cardiovascular disease
  Combined immunodeficiency due to STK4 deficiency
  Congestive heart failure
  Hepatocellular carcinoma
  Laryngeal carcinoma
  Liver cancer
  Neoplasm
  Obesity
  Coronary atherosclerosis
  Myocardial ischemia
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Chronic obstructive pulmonary disease
• UniProt ID: FUND1_HUMAN
• PDB ID: 2N9X; 5GMV
• Pfam ID: PF04930
• Sequence:
  MATRNPPPQDYESDDDSYEVLDLTEYARRHQWWNRVFGHSSGPMVEKYSVATQIVMGGVT
  GWCAGFLFQKVGKLAATAVGGGFLLLQIASHSGYVQIDWKRVEKDVNKAKRQIKKRANKA
  APEINNLIEEATEFIKQNIVISSGFVGGFLLGLAS
• Function: Integral mitochondrial outer-membrane protein that mediates the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs). In turn, mediates angiogenesis and neoangiogenesis through interference with intracellular Ca(2+) communication and regulation of the vascular endothelial growth factor receptor KDR/VEGFR2 expression at both mRNA and protein levels. Acts also as an activator of hypoxia-induced mitophagy, an important mechanism for mitochondrial quality and homeostasis, by interacting with and recruiting LC3 protein family to mitochondria. Mechanistically, recruits DRP1 at ER-mitochondria contact sites leading to DRP1 oligomerization and GTPase activity to facilitate mitochondrial fission during hypoxia. Additionally, plays a role in hepatic ferroptosis by interacting directly with glutathione peroxidase/GPX4 to facilitate its recruitment into mitochondria through TOM/TIM complex where it is degraded by mitophagy.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Mitophagy - animal (hsa04137)
• Reactome Pathway: Receptor Mediated Mitophagy (R-HSA-8934903)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Type-1/2 diabetes	DISIUHAP	Definitive	Altered Expression	[1]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[2]
Cardiac failure	DISDC067	Strong	Altered Expression	[3]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[4]
Combined immunodeficiency due to STK4 deficiency	DISYACRR	Strong	Biomarker	[5]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Laryngeal carcinoma	DISNHCIV	Strong	Biomarker	[6]
Liver cancer	DISDE4BI	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Obesity	DIS47Y1K	Strong	Biomarker	[7]
Coronary atherosclerosis	DISKNDYU	moderate	Biomarker	[8]
Myocardial ischemia	DISFTVXF	moderate	Biomarker	[8]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[9]
Breast cancer	DIS7DPX1	Limited	Biomarker	[10]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[10]
Cervical cancer	DISFSHPF	Limited	Altered Expression	[9]
Cervical carcinoma	DIST4S00	Limited	Altered Expression	[9]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of FUN14 domain-containing protein 1 (FUNDC1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of FUN14 domain-containing protein 1 (FUNDC1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of FUN14 domain-containing protein 1 (FUNDC1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of FUN14 domain-containing protein 1 (FUNDC1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of FUN14 domain-containing protein 1 (FUNDC1).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of FUN14 domain-containing protein 1 (FUNDC1).	[16]
Marinol	DM70IK5	Approved	Marinol increases the expression of FUN14 domain-containing protein 1 (FUNDC1).	[17]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of FUN14 domain-containing protein 1 (FUNDC1).	[18]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of FUN14 domain-containing protein 1 (FUNDC1).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of FUN14 domain-containing protein 1 (FUNDC1).	[21]

References

• [1] Hyperglycemia-Driven Inhibition of AMP-Activated Protein Kinase 2 Induces Diabetic Cardiomyopathy by Promoting Mitochondria-Associated Endoplasmic Reticulum Membranes In Vivo.Circulation. 2019 Apr 16;139(16):1913-1936. doi: 10.1161/CIRCULATIONAHA.118.033552.
• [2] FUN14 Domain-Containing 1-Mediated Mitophagy Suppresses Hepatocarcinogenesis by Inhibition of Inflammasome Activation in Mice.Hepatology. 2019 Feb;69(2):604-621. doi: 10.1002/hep.30191. Epub 2019 Jan 7.
• [3] Binding of FUN14 Domain Containing 1 With Inositol 1,4,5-Trisphosphate Receptor in Mitochondria-Associated Endoplasmic Reticulum Membranes Maintains Mitochondrial Dynamics and Function in Hearts in Vivo.Circulation. 2017 Dec 5;136(23):2248-2266. doi: 10.1161/CIRCULATIONAHA.117.030235. Epub 2017 Sep 23.
• [4] Mitophagy receptor FUNDC1 regulates mitochondrial homeostasis and protects the heart from I/R injury.Autophagy. 2017 Jun 3;13(6):1080-1081. doi: 10.1080/15548627.2017.1300224. Epub 2017 Mar 21.
• [5] Mst1 promotes cardiac ischemia-reperfusion injury by inhibiting the ERK-CREB pathway and repressing FUNDC1-mediated mitophagy.J Physiol Sci. 2019 Jan;69(1):113-127. doi: 10.1007/s12576-018-0627-3. Epub 2018 Jun 30.
• [6] Hydrogen peroxide-induced mitophagy contributes to laryngeal cancer cells survival via the upregulation of FUNDC1.Clin Transl Oncol. 2019 May;21(5):596-606. doi: 10.1007/s12094-018-1958-5. Epub 2018 Oct 3.
• [7] Deficiency of mitophagy receptor FUNDC1 impairs mitochondrial quality and aggravates dietary-induced obesity and metabolic syndrome.Autophagy. 2019 Nov;15(11):1882-1898. doi: 10.1080/15548627.2019.1596482. Epub 2019 Apr 6.
• [8] Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2-disturbed mitochondrial homeostasis via suppression of FUNDC1-related mitophagy.Cell Death Differ. 2018 Jun;25(6):1080-1093. doi: 10.1038/s41418-018-0086-7. Epub 2018 Mar 14.
• [9] High expression of FUNDC1 predicts poor prognostic outcomes and is a promising target to improve chemoradiotherapy effects in patients with cervical cancer.Cancer Med. 2017 Aug;6(8):1871-1881. doi: 10.1002/cam4.1112. Epub 2017 Jul 18.
• [10] FUN14 domain-containing 1 promotes breast cancer proliferation and migration by activating calcium-NFATC1-BMI1 axis.EBioMedicine. 2019 Mar;41:384-394. doi: 10.1016/j.ebiom.2019.02.032. Epub 2019 Feb 23.
• [11] Silencing FUNDC1 alleviates chronic obstructive pulmonary disease by inhibiting mitochondrial autophagy and bronchial epithelium cell apoptosis under hypoxic environment.J Cell Biochem. 2019 Oct;120(10):17602-17615. doi: 10.1002/jcb.29028. Epub 2019 Jun 25.
• [12] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [18] Berbamine Hydrochloride inhibits lysosomal acidification by activating Nox2 to potentiate chemotherapy-induced apoptosis via the ROS-MAPK pathway in human lung carcinoma cells. Cell Biol Toxicol. 2023 Aug;39(4):1297-1317. doi: 10.1007/s10565-022-09756-8. Epub 2022 Sep 7.
• [19] 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.
• [20] FUNDC1 regulates receptor-mediated mitophagy independently of the PINK1/Parkin-dependent pathway in rotenone-treated SH-SY5Y cells. Food Chem Toxicol. 2020 Mar;137:111163. doi: 10.1016/j.fct.2020.111163. Epub 2020 Jan 27.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.