Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJMHX1V)

• DOT Name: Mitochondrial import inner membrane translocase subunit Tim22 (TIMM22)
• Synonyms: Testis-expressed protein 4
• Gene Name: TIMM22
• Related Disease:
  Mitochondrial myopathy
  Sengers syndrome
  Combined oxidative phosphorylation deficiency 43
• UniProt ID: TIM22_HUMAN
• PDB ID: 7CGP
• Pfam ID: PF02466
• Sequence:
  MAAAAPNAGGSAPETAGSAEAPLQYSLLLQYLVGDKRQPRLLEPGSLGGIPSPAKSEEQK
  MIEKAMESCAFKAALACVGGFVLGGAFGVFTAGIDTNVGFDPKDPYRTPTAKEVLKDMGQ
  RGMSYAKNFAIVGAMFSCTECLIESYRGTSDWKNSVISGCITGGAIGFRAGLKAGAIGCG
  GFAAFSAAIDYYLR
• Function: Essential core component of the TIM22 complex, a complex that mediates the import and insertion of multi-pass transmembrane proteins into the mitochondrial inner membrane. In the TIM22 complex, it constitutes the voltage-activated and signal-gated channel. Forms a twin-pore translocase that uses the membrane potential as external driving force in 2 voltage-dependent steps.
• Reactome Pathway: 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
Mitochondrial myopathy	DIS9SA7V	Strong	Genetic Variation	[1]
Sengers syndrome	DISV24KG	Strong	Biomarker	[2]
Combined oxidative phosphorylation deficiency 43	DIS3KC3C	Limited	Autosomal recessive	[3]

6 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 Tim22 (TIMM22).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Mitochondrial import inner membrane translocase subunit Tim22 (TIMM22).	[5]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Mitochondrial import inner membrane translocase subunit Tim22 (TIMM22).	[6]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Mitochondrial import inner membrane translocase subunit Tim22 (TIMM22).	[7]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Mitochondrial import inner membrane translocase subunit Tim22 (TIMM22).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mitochondrial import inner membrane translocase subunit Tim22 (TIMM22).	[9]

References

• [1] Mutations of the mitochondrial carrier translocase channel subunit TIM22 cause early-onset mitochondrial myopathy. Hum Mol Genet. 2018 Dec 1;27(23):4135-4144. doi: 10.1093/hmg/ddy305.
• [2] Acylglycerol Kinase Mutated in Sengers Syndrome Is a Subunit of the TIM22 Protein Translocase in Mitochondria. Mol Cell. 2017 Aug 3;67(3):471-483.e7.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [7] Proteomic analysis of anti-cancer effects by paclitaxel treatment in cervical cancer cells. Gynecol Oncol. 2005 Jul;98(1):45-53. doi: 10.1016/j.ygyno.2005.04.010.
• [8] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.