Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ185UW)

• DOT Name: Mitochondrial intermembrane space import and assembly protein 40 (CHCHD4)
• Synonyms: Coiled-coil-helix-coiled-coil-helix domain-containing protein 4
• Gene Name: CHCHD4
• Related Disease:
  Neoplasm
  Friedreich ataxia 1
• UniProt ID: MIA40_HUMAN
• PDB ID: 2K3J; 2L0Y
• Pfam ID: PF06747
• Sequence:
  MSYCRQEGKDRIIFVTKEDHETPSSAELVADDPNDPYEEHGLILPNGNINWNCPCLGGMA
  SGPCGEQFKSAFSCFHYSTEEIKGSDCVDQFRAMQECMQKYPDLYPQEDEDEEEEREKKP
  AEQAEETAPIEATATKEEEGSS
• Function: Central component of a redox-sensitive mitochondrial intermembrane space import machinery which is required for the biogenesis of respiratory chain complexes. Functions as chaperone and catalyzes the formation of disulfide bonds in substrate proteins, such as COX17, COX19, MICU1 and COA7. Required for the import and folding of small cysteine-containing proteins (small Tim) in the mitochondrial intermembrane space (IMS). Required for the import of COA7 in the IMS. Precursor proteins to be imported into the IMS are translocated in their reduced form into the mitochondria. The oxidized form of CHCHD4/MIA40 forms a transient intermolecular disulfide bridge with the reduced precursor protein, resulting in oxidation of the precursor protein that now contains an intramolecular disulfide bond and is able to undergo folding in the IMS. Reduced CHCHD4/MIA40 is then reoxidized by GFER/ERV1 via a disulfide relay system. Mediates formation of disulfide bond in MICU1 in the IMS, promoting formation of the MICU1-MICU2 heterodimer that regulates mitochondrial calcium uptake.
• Tissue Specificity: Expressed in all tissues tested, suggesting an ubiquitous expression.
• Reactome Pathway: Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Friedreich ataxia 1	DIS285GE	Strong	Biomarker	[2]

8 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 intermembrane space import and assembly protein 40 (CHCHD4).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial intermembrane space import and assembly protein 40 (CHCHD4).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial intermembrane space import and assembly protein 40 (CHCHD4).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitochondrial intermembrane space import and assembly protein 40 (CHCHD4).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Mitochondrial intermembrane space import and assembly protein 40 (CHCHD4).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mitochondrial intermembrane space import and assembly protein 40 (CHCHD4).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Mitochondrial intermembrane space import and assembly protein 40 (CHCHD4).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mitochondrial intermembrane space import and assembly protein 40 (CHCHD4).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Mitochondrial intermembrane space import and assembly protein 40 (CHCHD4).	[7]

References

• [1] Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression.J Clin Invest. 2012 Feb;122(2):600-11. doi: 10.1172/JCI58780. Epub 2012 Jan 3.
• [2] Quantitative proteomics in Friedreich's ataxia B-lymphocytes: A valuable approach to decipher the biochemical events responsible for pathogenesis.Biochim Biophys Acta Mol Basis Dis. 2018 Apr;1864(4 Pt A):997-1009. doi: 10.1016/j.bbadis.2018.01.010. Epub 2018 Jan 9.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.