Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLA1V91)

• DOT Name: Mitochondrial import inner membrane translocase subunit TIM14 (DNAJC19)
• Synonyms: DnaJ homolog subfamily C member 19
• Gene Name: DNAJC19
• Related Disease:
  3-methylglutaconic aciduria type 5
  Cerebellar ataxia
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  3-methylglutaconic aciduria
  Cardiomyopathy
  Deafness dystonia syndrome
• UniProt ID: TIM14_HUMAN
• Pfam ID: PF00226
• Sequence:
  MASTVVAVGLTIAAAGFAGRYVLQAMKHMEPQVKQVFQSLPKSAFSGGYYRGGFEPKMTK
  REAALILGVSPTANKGKIRDAHRRIMLLNHPDKGGSPYIAAKINEAKDLLEGQAKK
• Function: Mitochondrial co-chaperone which forms a complex with prohibitins to regulate cardiolipin remodeling. May be a component of the PAM complex, a complex required for the translocation of transit peptide-containing proteins from the inner membrane into the mitochondrial matrix in an ATP-dependent manner. May act as a co-chaperone that stimulate the ATP-dependent activity.
• Tissue Specificity: Ubiquitously expressed.
• Reactome Pathway: Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
3-methylglutaconic aciduria type 5	DISEP4OP	Definitive	Autosomal recessive	[1]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[2]
Dilated cardiomyopathy	DISX608J	Strong	Biomarker	[3]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[4]
3-methylglutaconic aciduria	DIS8G1WP	moderate	Genetic Variation	[5]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[6]
Deafness dystonia syndrome	DIS0480U	Limited	Biomarker	[2]

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 Mitochondrial import inner membrane translocase subunit TIM14 (DNAJC19).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mitochondrial import inner membrane translocase subunit TIM14 (DNAJC19).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitochondrial import inner membrane translocase subunit TIM14 (DNAJC19).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial import inner membrane translocase subunit TIM14 (DNAJC19).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial import inner membrane translocase subunit TIM14 (DNAJC19).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial import inner membrane translocase subunit TIM14 (DNAJC19).	[12]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Mitochondrial import inner membrane translocase subunit TIM14 (DNAJC19).	[13]
Nefazodone	DM4ZS8M	Approved	Nefazodone decreases the expression of Mitochondrial import inner membrane translocase subunit TIM14 (DNAJC19).	[14]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Mitochondrial import inner membrane translocase subunit TIM14 (DNAJC19).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Mitochondrial import inner membrane translocase subunit TIM14 (DNAJC19).	[16]

References

• [1] 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.
• [2] Underappreciated Roles of the Translocase of the Outer and Inner Mitochondrial Membrane Protein Complexes in Human Disease.DNA Cell Biol. 2019 Jan;38(1):23-40. doi: 10.1089/dna.2018.4292. Epub 2018 Nov 27.
• [3] Progressive Cerebellar Atrophy and a Novel Homozygous Pathogenic DNAJC19 Variant as a Cause of Dilated Cardiomyopathy Ataxia Syndrome.Pediatr Neurol. 2016 Sep;62:58-61. doi: 10.1016/j.pediatrneurol.2016.03.020. Epub 2016 Jun 4.
• [4] Role of Magmas in protein transport and human mitochondria biogenesis.Hum Mol Genet. 2010 Apr 1;19(7):1248-62. doi: 10.1093/hmg/ddq002. Epub 2010 Jan 6.
• [5] Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit. Eur J Hum Genet. 2016 Dec;24(12):1778-1782. doi: 10.1038/ejhg.2016.83. Epub 2016 Aug 3.
• [6] DNAJC19, a mitochondrial cochaperone associated with cardiomyopathy, forms a complex with prohibitins to regulate cardiolipin remodeling.Cell Metab. 2014 Jul 1;20(1):158-71. doi: 10.1016/j.cmet.2014.04.016. Epub 2014 May 22.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [10] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [14] Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. Arch Toxicol. 2020 Apr;94(4):1151-1172. doi: 10.1007/s00204-020-02691-9. Epub 2020 Mar 10.
• [15] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.