Exposure of PC12 cells to reagent peroxynitrite promotes the release of arachidonic acid (AA) mediated by activation of phospholipase A2 [Guidarelli, Palomba and Cantoni (2000) Br. J. Pharmacol. 129, 1539–1542]. We now present experimental evidence consistent with the notion that this response is not directly triggered by peroxynitrite but, rather, by reactive oxygen species generated at the level of complex III of the mitochondrial respiratory chain. In particular, superoxide (and not hydrogen peroxide) has a pivotal role in peroxynitrite-dependent activation of phospholipase A2. This observation was confirmed by results showing that superoxide, or peroxynitrite, promotes release of AA in isolated mitochondria. Consistently, the release of AA elicited by either peroxynitrite or A23187 in intact cells was shown to be calcium-dependent and differentially affected by phospholipase A2 inhibitors with different levels of specificity. In particular, the effects of peroxynitrite, unlike those of A23187, were both sensitive to low concentrations of two general phospholipase A2 inhibitors and insensitive to arachidonyltrifluoromethyl ketone, which shows some selectivity towards cytosolic phospholipase A2. In addition, peroxynitrite and A23187 synergistically enhanced the release of AA. Collectively, the above results demonstrate that peroxynitrite causes inhibition of complex III, followed by enforced formation of superoxides that stimulate the activity of a calcium-dependent PLA2 isoform, probably localized in the mitochondria.
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August 2002
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Research Article|
August 15 2002
Pivotal role of superoxides generated in the mitochondrial respiratory chain in peroxynitrite-dependent activation of phospholipase A2
Andrea GUIDARELLI;
Andrea GUIDARELLI
Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino, Via S. Chiara 27, 61029 Urbino (PU), Italy
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Orazio CANTONI
Orazio CANTONI
1
Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino, Via S. Chiara 27, 61029 Urbino (PU), Italy
1To whom correspondence should be addressed (e-mail cantoni@uniurb.it).
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Publisher: Portland Press Ltd
Received:
February 18 2002
Revision Received:
April 29 2002
Accepted:
May 07 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 366 (1): 307–314.
Article history
Received:
February 18 2002
Revision Received:
April 29 2002
Accepted:
May 07 2002
Citation
Andrea GUIDARELLI, Orazio CANTONI; Pivotal role of superoxides generated in the mitochondrial respiratory chain in peroxynitrite-dependent activation of phospholipase A2. Biochem J 15 August 2002; 366 (1): 307–314. doi: https://doi.org/10.1042/bj20020284
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