Mitochondrial targeting of the electrophilic lipid 15-deoxy-Δ^12,14prostaglandin J₂ increases apoptotic efficacy via redox cell signalling mechanisms

Prototypical electrophiles such as the lipid 15-deoxy-Δ^12,14-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.