The molecular mechanisms underlying the initiation and control of the release of cytochrome c during mitochondrion-dependent apoptosis are thought to involve the phosphorylation of mitochondrial Bcl-2 and Bcl-xL. Although the c-Jun N-terminal kinase (JNK) has been proposed to mediate the phosphorylation of Bcl-2/Bcl-xL the mechanisms linking the modification of these proteins and the release of cytochrome c remain to be elucidated. This study was aimed at establishing interdependency between JNK signalling and mitochondrial apoptosis. Using an experimental model consisting of isolated, bioenergetically competent rat brain mitochondria, these studies show that (i) JNK catalysed the phosphorylation of Bcl-2 and Bcl-xL as well as other mitochondrial proteins, as shown by two-dimensional isoelectric focusing/SDS/PAGE; (ii) JNK-induced cytochrome c release, in a process independent of the permeability transition of the inner mitochondrial membrane (imPT) and insensitive to cyclosporin A; (iii) JNK mediated a partial collapse of the mitochondrial inner-membrane potential (Δψm) in an imPT- and cyclosporin A-independent manner; and (iv) JNK was unable to induce imPT/swelling and did not act as a co-inducer, but as an inhibitor of Ca-induced imPT. The results are discussed with regard to the functional link between the Δψm and factors influencing the permeability transition of the inner and outer mitochondrial membranes. Taken together, JNK-dependent phosphorylation of mitochondrial proteins including, but not limited to, Bcl-2/Bcl-xL may represent a potential of the modulation of mitochondrial function during apoptosis.
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June 2003
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Research Article|
June 01 2003
c-Jun N-terminal kinase (JNK)-mediated modulation of brain mitochondria function: new target proteins for JNK signalling in mitochondrion-dependent apoptosis
Hagen SCHROETER;
Hagen SCHROETER
∗Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089-9121, U.S.A.
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Clinton S. BOYD;
Clinton S. BOYD
∗Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089-9121, U.S.A.
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Ruhi AHMED;
Ruhi AHMED
∗Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089-9121, U.S.A.
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Jeremy P. E. SPENCER;
Jeremy P. E. SPENCER
†Wolfson Centre for Age-Related Diseases, School of Biomedical Sciences, King's College, London SE1 9RT, U.K.
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Roger F. DUNCAN;
Roger F. DUNCAN
∗Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089-9121, U.S.A.
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Catherine RICE-EVANS;
Catherine RICE-EVANS
†Wolfson Centre for Age-Related Diseases, School of Biomedical Sciences, King's College, London SE1 9RT, U.K.
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Enrique CADENAS
Enrique CADENAS
1
∗Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089-9121, U.S.A.
1To whom correspondence should be addressed (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
February 03 2003
Revision Received:
February 24 2003
Accepted:
March 04 2003
Accepted Manuscript online:
March 04 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 372 (2): 359–369.
Article history
Received:
February 03 2003
Revision Received:
February 24 2003
Accepted:
March 04 2003
Accepted Manuscript online:
March 04 2003
Citation
Hagen SCHROETER, Clinton S. BOYD, Ruhi AHMED, Jeremy P. E. SPENCER, Roger F. DUNCAN, Catherine RICE-EVANS, Enrique CADENAS; c-Jun N-terminal kinase (JNK)-mediated modulation of brain mitochondria function: new target proteins for JNK signalling in mitochondrion-dependent apoptosis. Biochem J 1 June 2003; 372 (2): 359–369. doi: https://doi.org/10.1042/bj20030201
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