Document Detail


Mitochondrial targeting of the electrophilic lipid 15-deoxy-Delta12,14-prostaglandin J2 increases apoptotic efficacy via redox cell signalling mechanisms.
MedLine Citation:
PMID:  19916962     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Prototypical electrophiles such as the lipid 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) are well recognized for their therapeutic potential. Electrophiles modify signalling proteins in both the cytosol and mitochondrion, which results in diverse cellular responses, including cytoprotective effects and, at high doses, cell death. These findings led us to the hypothesis that targeting electrophiles to specific compartments in the cell could fine-tune their biological effects. To examine this, we synthesized a novel mitochondrially targeted analogue of 15d-PGJ2 (mito-15d-PGJ2) and tested its effects on redox cell signalling. Mito-15d-PGJ2 caused profound defects in mitochondrial bioenergetics and mitochondrial membrane depolarization when compared with 15d-PGJ2. We also found that mito-15d-PGJ2 modified different members of the electrophile-responsive proteome, was more potent at initiating intrinsic apoptotic cell death and was less effective than 15d-PGJ2 at up-regulating the expression of HO-1 (haem oxygenase-1) and glutathione. These results demonstrate the feasibility of modulating the biological effects of electrophiles by targeting the pharmacophore to mitochondria.
Authors:
Anne R Diers; Ashlee N Higdon; Karina C Ricart; Michelle S Johnson; Anupam Agarwal; Balaraman Kalyanaraman; Aimee Landar; Victor M Darley-Usmar
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-01-27
Journal Detail:
Title:  The Biochemical journal     Volume:  426     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-01-27     Completed Date:  2010-02-16     Revised Date:  2014-09-15    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  31-41     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects*
Blotting, Western
Cell Line
Cell Line, Tumor
Cell Survival / drug effects
Glutathione / metabolism
Heme Oxygenase-1 / metabolism
Humans
Intracellular Signaling Peptides and Proteins / genetics,  metabolism
Membrane Potential, Mitochondrial
Mitochondria / drug effects*,  metabolism*
Oxidation-Reduction / drug effects
Prostaglandin D2 / analogs & derivatives*,  pharmacology
Signal Transduction / drug effects
Grant Support
ID/Acronym/Agency:
DK 079337/DK/NIDDK NIH HHS; DK 75865/DK/NIDDK NIH HHS; ES10167/ES/NIEHS NIH HHS; P30 DK079337/DK/NIDDK NIH HHS; P30 DK079337-04/DK/NIDDK NIH HHS; R01 DK075865/DK/NIDDK NIH HHS; R01 DK075865-04/DK/NIDDK NIH HHS; R01 ES010167/ES/NIEHS NIH HHS; R01 ES010167-10/ES/NIEHS NIH HHS; T32 HL007918/HL/NHLBI NIH HHS; T32 HL007918/HL/NHLBI NIH HHS; T32 HL007918-13/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/15-deoxyprostaglandin J2; 0/Intracellular Signaling Peptides and Proteins; 0/KEAP1 protein, human; EC 1.14.99.3/Heme Oxygenase-1; GAN16C9B8O/Glutathione; RXY07S6CZ2/Prostaglandin D2
Comments/Corrections

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