Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT665WYT)

• DOT Name: Lon protease homolog, mitochondrial (LONP1)
• Synonyms: EC 3.4.21.53; LONHs; Lon protease-like protein; LONP; Mitochondrial ATP-dependent protease Lon; Serine protease 15
• Gene Name: LONP1
• Related Disease:
  CODAS syndrome
  Pyruvate dehydrogenase E1-alpha deficiency
  Leigh syndrome
• UniProt ID: LONM_HUMAN
• PDB ID: 2X36; 6WYS; 6WZV; 6X1M; 6X27; 7KRZ; 7KSL; 7KSM; 7NFY; 7NG4; 7NG5; 7NGC; 7NGF; 7NGL; 7NGP; 7NGQ; 7OXO; 7P09; 7P0B; 7P0M
• EC Number: 3.4.21.53
• Pfam ID: PF00004 ; PF05362 ; PF02190
• Sequence:
  MAASTGYVRLWGAARCWVLRRPMLAAAGGRVPTAAGAWLLRGQRTCDASPPWALWGRGPA
  IGGQWRGFWEASSRGGGAFSGGEDASEGGAEEGAGGAGGSAGAGEGPVITALTPMTIPDV
  FPHLPLIAITRNPVFPRFIKIIEVKNKKLVELLRRKVRLAQPYVGVFLKRDDSNESDVVE
  SLDEIYHTGTFAQIHEMQDLGDKLRMIVMGHRRVHISRQLEVEPEEPEAENKHKPRRKSK
  RGKKEAEDELSARHPAELAMEPTPELPAEVLMVEVENVVHEDFQVTEEVKALTAEIVKTI
  RDIIALNPLYRESVLQMMQAGQRVVDNPIYLSDMGAALTGAESHELQDVLEETNIPKRLY
  KALSLLKKEFELSKLQQRLGREVEEKIKQTHRKYLLQEQLKIIKKELGLEKDDKDAIEEK
  FRERLKELVVPKHVMDVVDEELSKLGLLDNHSSEFNVTRNYLDWLTSIPWGKYSNENLDL
  ARAQAVLEEDHYGMEDVKKRILEFIAVSQLRGSTQGKILCFYGPPGVGKTSIARSIARAL
  NREYFRFSVGGMTDVAEIKGHRRTYVGAMPGKIIQCLKKTKTENPLILIDEVDKIGRGYQ
  GDPSSALLELLDPEQNANFLDHYLDVPVDLSKVLFICTANVTDTIPEPLRDRMEMINVSG
  YVAQEKLAIAERYLVPQARALCGLDESKAKLSSDVLTLLIKQYCRESGVRNLQKQVEKVL
  RKSAYKIVSGEAESVEVTPENLQDFVGKPVFTVERMYDVTPPGVVMGLAWTAMGGSTLFV
  ETSLRRPQDKDAKGDKDGSLEVTGQLGEVMKESARIAYTFARAFLMQHAPANDYLVTSHI
  HLHVPEGATPKDGPSAGCTIVTALLSLAMGRPVRQNLAMTGEVSLTGKILPVGGIKEKTI
  AAKRAGVTCIVLPAENKKDFYDLAAFITEGLEVHFVEHYREIFDIAFPDEQAEALAVER
• Function: ATP-dependent serine protease that mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides as well as certain short-lived regulatory proteins in the mitochondrial matrix. Endogenous substrates include mitochondrial steroidogenic acute regulatory (StAR) protein, DELE1, helicase Twinkle (TWNK) and the large ribosomal subunit protein MRPL32/bL32m. MRPL32/bL32m is protected from degradation by LONP1 when it is bound to a nucleic acid (RNA), but TWNK is not. May also have a chaperone function in the assembly of inner membrane protein complexes. Participates in the regulation of mitochondrial gene expression and in the maintenance of the integrity of the mitochondrial genome. Binds to mitochondrial promoters and RNA in a single-stranded, site-specific, and strand-specific manner. May regulate mitochondrial DNA replication and/or gene expression using site-specific, single-stranded DNA binding to target the degradation of regulatory proteins binding to adjacent sites in mitochondrial promoters.
• Tissue Specificity: Duodenum, heart, lung and liver, but not thymus.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
CODAS syndrome	DISLB5OT	Strong	Autosomal recessive	[1]
Pyruvate dehydrogenase E1-alpha deficiency	DISZ6WMJ	Supportive	X-linked	[2]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[3]

18 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 Lon protease homolog, mitochondrial (LONP1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Lon protease homolog, mitochondrial (LONP1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lon protease homolog, mitochondrial (LONP1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Lon protease homolog, mitochondrial (LONP1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of Lon protease homolog, mitochondrial (LONP1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Lon protease homolog, mitochondrial (LONP1).	[9]
Marinol	DM70IK5	Approved	Marinol increases the expression of Lon protease homolog, mitochondrial (LONP1).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Lon protease homolog, mitochondrial (LONP1).	[11]
Zidovudine	DM4KI7O	Approved	Zidovudine affects the expression of Lon protease homolog, mitochondrial (LONP1).	[12]
Efavirenz	DMC0GSJ	Approved	Efavirenz increases the expression of Lon protease homolog, mitochondrial (LONP1).	[13]
Stavudine	DM6DEK9	Approved	Stavudine affects the expression of Lon protease homolog, mitochondrial (LONP1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Lon protease homolog, mitochondrial (LONP1).	[14]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the expression of Lon protease homolog, mitochondrial (LONP1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lon protease homolog, mitochondrial (LONP1).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Lon protease homolog, mitochondrial (LONP1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Lon protease homolog, mitochondrial (LONP1).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Lon protease homolog, mitochondrial (LONP1).	[19]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Lon protease homolog, mitochondrial (LONP1).	[20]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Bi-allelic mutations of LONP1 encoding the mitochondrial LonP1 protease cause pyruvate dehydrogenase deficiency and profound neurodegeneration with progressive cerebellar atrophy. Hum Mol Genet. 2019 Jan 15;28(2):290-306. doi: 10.1093/hmg/ddy351.
• [3] 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.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Antihypertrophic Effects of Small Molecules that Maintain Mitochondrial ATP Levels Under Hypoxia. EBioMedicine. 2017 Oct;24:147-158. doi: 10.1016/j.ebiom.2017.09.022. Epub 2017 Sep 19.
• [9] 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.
• [10] Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes. Brain Res. 2008 Jan 29;1191:1-11.
• [11] 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.
• [12] Lon protease and eiF2 are involved in acute, but not prolonged, antiretroviral induced stress response in HepG2 cells. Chem Biol Interact. 2016 May 25;252:82-6. doi: 10.1016/j.cbi.2016.03.021. Epub 2016 Apr 1.
• [13] Lon protease: a novel mitochondrial matrix protein in the interconnection between drug-induced mitochondrial dysfunction and endoplasmic reticulum stress. Br J Pharmacol. 2017 Dec;174(23):4409-4429. doi: 10.1111/bph.14045. Epub 2017 Nov 7.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Lonp1 and Sig-1R contribute to the counteraction of ursolic acid against ochratoxin A-induced mitochondrial apoptosis. Food Chem Toxicol. 2023 Feb;172:113592. doi: 10.1016/j.fct.2022.113592. Epub 2022 Dec 29.
• [16] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [17] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [20] Glucose-regulated protein 75 in foodborne disease models induces renal tubular necrosis. Food Chem Toxicol. 2019 Nov;133:110720. doi: 10.1016/j.fct.2019.110720. Epub 2019 Jul 29.