Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIK4I5R)

• DOT Name: Complex I assembly factor TIMMDC1, mitochondrial (TIMMDC1)
• Synonyms: Protein M5-14; Translocase of inner mitochondrial membrane domain-containing protein 1; TIMM domain containing-protein 1
• Gene Name: TIMMDC1
• Related Disease:
  Asthma
  Hypothyroidism
  Juvenile idiopathic arthritis
  Lung carcinoma
  Mitochondrial complex 1 deficiency, nuclear type 31
  Multiple sclerosis
  Primary biliary cholangitis
  Mitochondrial complex I deficiency
  Gastric cancer
  Leigh syndrome
  Stomach cancer
  Systemic lupus erythematosus
• UniProt ID: TIDC1_HUMAN
• Pfam ID: PF02466
• Sequence:
  MEVPPPAPRSFLCRALCLFPRVFAAEAVTADSEVLEERQKRLPYVPEPYYPESGWDRLRE
  LFGKDEQQRISKDLANICKTAATAGIIGWVYGGIPAFIHAKQQYIEQSQAEIYHNRFDAV
  QSAHRAATRGFIRYGWRWGWRTAVFVTIFNTVNTSLNVYRNKDALSHFVIAGAVTGSLFR
  INVGLRGLVAGGIIGALLGTPVGGLLMAFQKYSGETVQERKQKDRKALHELKLEEWKGRL
  QVTEHLPEKIESSLQEDEPENDAKKIEALLNLPRNPSVIDKQDKD
• Function: Chaperone protein involved in the assembly of the mitochondrial NADH:ubiquinone oxidoreductase complex (complex I). Participates in constructing the membrane arm of complex I.
• Tissue Specificity: Generalized expression enhanced in heart and skeletal muscle.
• Reactome Pathway: Complex I biogenesis (R-HSA-6799198)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma	DISW9QNS	Definitive	Altered Expression	[1]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[2]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Genetic Variation	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[4]
Mitochondrial complex 1 deficiency, nuclear type 31	DISQ7R0C	Strong	Autosomal recessive	[5]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[6]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[7]
Mitochondrial complex I deficiency	DIS13M7V	Supportive	Autosomal recessive	[5]
Gastric cancer	DISXGOUK	Limited	Biomarker	[8]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[9]
Stomach cancer	DISKIJSX	Limited	Biomarker	[8]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Complex I assembly factor TIMMDC1, mitochondrial (TIMMDC1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Complex I assembly factor TIMMDC1, mitochondrial (TIMMDC1).	[16]

6 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 Complex I assembly factor TIMMDC1, mitochondrial (TIMMDC1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Complex I assembly factor TIMMDC1, mitochondrial (TIMMDC1).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Complex I assembly factor TIMMDC1, mitochondrial (TIMMDC1).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Complex I assembly factor TIMMDC1, mitochondrial (TIMMDC1).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Complex I assembly factor TIMMDC1, mitochondrial (TIMMDC1).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Complex I assembly factor TIMMDC1, mitochondrial (TIMMDC1).	[18]

References

• [1] Long non-coding RNA TCF7 contributes to the growth and migration of airway smooth muscle cells in asthma through targeting TIMMDC1/Akt axis.Biochem Biophys Res Commun. 2019 Jan 15;508(3):749-755. doi: 10.1016/j.bbrc.2018.11.187. Epub 2018 Dec 6.
• [2] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [3] Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13.Arthritis Rheum. 2012 Aug;64(8):2781-91. doi: 10.1002/art.34429.
• [4] Depletion of C3orf1/TIMMDC1 inhibits migration and proliferation in 95D lung carcinoma cells.Int J Mol Sci. 2014 Nov 10;15(11):20555-71. doi: 10.3390/ijms151120555.
• [5] Genetic diagnosis of Mendelian disorders via RNA sequencing. Nat Commun. 2017 Jun 12;8:15824. doi: 10.1038/ncomms15824.
• [6] Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.Nat Genet. 2013 Nov;45(11):1353-60. doi: 10.1038/ng.2770. Epub 2013 Sep 29.
• [7] POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33.Sci Rep. 2019 Jan 14;9(1):102. doi: 10.1038/s41598-018-36490-1.
• [8] TIMMDC1 Knockdown Inhibits Growth and Metastasis of Gastric Cancer Cells through Metabolic Inhibition and AKT/GSK3/-Catenin Signaling Pathway.Int J Biol Sci. 2018 Jul 27;14(10):1256-1267. doi: 10.7150/ijbs.27100. eCollection 2018.
• [9] 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.
• [10] Transancestral mapping and genetic load in systemic lupus erythematosus.Nat Commun. 2017 Jul 17;8:16021. doi: 10.1038/ncomms16021.
• [11] 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.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] 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.
• [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] 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.
• [17] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.