Prototypical electrophiles such as the lipid 15-deoxy-Δ12,14-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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February 2010
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Research Article|
January 27 2010
Mitochondrial targeting of the electrophilic lipid 15-deoxy-Δ12,14prostaglandin J2 increases apoptotic efficacy via redox cell signalling mechanisms
Anne R. Diers;
Anne R. Diers
*Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
†Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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Ashlee N. Higdon;
Ashlee N. Higdon
*Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
†Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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Karina C. Ricart;
Karina C. Ricart
*Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
†Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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Michelle S. Johnson;
Michelle S. Johnson
*Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
†Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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Anupam Agarwal;
Anupam Agarwal
*Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
‡Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
§Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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Balaraman Kalyanaraman;
Balaraman Kalyanaraman
‖Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
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Aimee Landar;
Aimee Landar
*Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
†Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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Victor M. Darley-Usmar
Victor M. Darley-Usmar
1
*Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
†Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
1To whom correspondence should be addressed (email darley@uab.edu).
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Biochem J (2010) 426 (1): 31–41.
Article history
Received:
August 18 2009
Revision Received:
October 30 2009
Accepted:
November 16 2009
Accepted Manuscript online:
November 16 2009
Citation
Anne R. Diers, Ashlee N. Higdon, Karina C. Ricart, Michelle S. Johnson, Anupam Agarwal, Balaraman Kalyanaraman, Aimee Landar, Victor M. Darley-Usmar; Mitochondrial targeting of the electrophilic lipid 15-deoxy-Δ12,14prostaglandin J2 increases apoptotic efficacy via redox cell signalling mechanisms. Biochem J 15 February 2010; 426 (1): 31–41. doi: https://doi.org/10.1042/BJ20091293
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