Mitochondrial targeting of the electrophilic lipid 15-deoxy-Delta12,14-prostaglandin J2 increases apoptotic efficacy via redox cell signalling mechanisms.

The Biochemical Journal
Anne R DiersVictor M Darley-Usmar

Abstract

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.

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Citations

Sep 28, 2010·The Journal of Biological Chemistry·Claudia R OlivaCorinne E Griguer
Feb 23, 2012·Antioxidants & Redox Signaling·Ashlee N HigdonVictor M Darley-Usmar
Jun 21, 2011·American Journal of Physiology. Heart and Circulatory Physiology·Anne R DiersNeil Hogg
Jan 17, 2012·American Journal of Physiology. Heart and Circulatory Physiology·Ashlee N HigdonVictor M Darley-Usmar
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Mar 1, 2012·The Biochemical Journal·Ashlee HigdonVictor M Darley-Usmar
May 15, 2013·Redox Biology·Colin ReilyVictor Darley-Usmar
Jan 30, 2015·Frontiers in Molecular Neuroscience·Maria E Figueiredo-PereiraPeter Serrano
May 25, 2013·Free Radical Biology & Medicine·Matthew DodsonJianhua Zhang
Oct 10, 2013·British Journal of Pharmacology·Sergiy M NadtochiyPaul S Brookes
Aug 6, 2014·British Journal of Pharmacology·Christine WasingerMartin Hohenegger
May 31, 2013·American Journal of Physiology. Renal Physiology·Subhashini BolisettyAnupam Agarwal
Jan 11, 2016·Annals of the New York Academy of Sciences·Maria E Figueiredo-PereiraJohn Babich
Mar 19, 2015·Molecular Cancer Research : MCR·Yuhong WeiMichael F Moran
Jan 23, 2021·RSC Medicinal Chemistry·Jiayao WangZhaohai Qin
Aug 3, 2021·Frontiers in Physiology·Bohae Rachel LeeNeelam Sharma-Walia

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