Mitochondrial targeting of the electrophilic lipid 15-deoxy-Delta12,14-prostaglandin J2 increases apoptotic efficacy via redox cell signalling mechanisms. Biochem J 2010 Jan 27;426(1):31-41
Date
11/18/2009Pubmed ID
19916962Pubmed Central ID
PMC3079364DOI
10.1042/BJ20091293Scopus ID
2-s2.0-76549096602 (requires institutional sign-in at Scopus site) 51 CitationsAbstract
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.
Author List
Diers AR, Higdon AN, Ricart KC, Johnson MS, Agarwal A, Kalyanaraman B, Landar A, Darley-Usmar VMAuthor
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ApoptosisBlotting, Western
Cell Line
Cell Line, Tumor
Cell Survival
Glutathione
Heme Oxygenase-1
Humans
Intracellular Signaling Peptides and Proteins
Kelch-Like ECH-Associated Protein 1
Membrane Potential, Mitochondrial
Mitochondria
Oxidation-Reduction
Prostaglandin D2
Signal Transduction