期刊
BIOCHEMICAL JOURNAL
卷 426, 期 -, 页码 31-41出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20091293
关键词
apoptosis; 15-deoxy-Delta(12,14)-prostaglandin J(2); haem(heme); mitochondrion; redox signalling; thiol
资金
- National Institutes of Health [ES10167, DK 75865, DK 079337, T32 HL007918]
- American Heart Association [0635361N, 0815177E]
Prototypical electrophiles such as the lipid 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) 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-PGJ(2) (mito-15d-PGJ(2)) and tested its effects on redox cell signalling. Mito-15d-PGJ(2) caused profound defects in mitochondrial bioenergetics and mitochondrial membrane depolarization when compared with 15d-PGJ(2). We also found that mito-15d-PGJ(2) modified different members of the electrophile-responsive proteome, was more potent at initiating intrinsic apoptotic cell death and was less effective than 15d-PGJ(2) at up-regulating the expression of HO-I (haem oxygenase-I) and glutathione. These results demonstrate the feasibility of modulating the biological effects of electrophiles by targeting the pharmacophore to mitochondria.
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