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J. Biol. Chem., Vol. 279, Issue 36, 37860-37869, September 3, 2004

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Rat Brain Cortex Mitochondria Release Group II Secretory Phospholipase A₂ under Reduced Membrane Potential^*

Lara Macchioni, Lanfranco Corazzi, Vincenza Nardicchi, Roberta Mannucci, Cataldo Arcuri¶, Serena Porcellati, Tito Sposini¶, Rosario Donato¶, and Gianfrancesco Goracci||

From the Department of Internal Medicine, Division of Biochemistry, Laboratory of Image Analysis, and ^¶Department of Experimental Medicine and Biochemical Sciences, University of Perugia, I-06125 Perugia, Italy

Activation of brain mitochondrial phospholipase(s) A₂ (PLA₂) might contribute to cell damage and be involved in neurodegeneration. Despite the potential importance of the phenomenon, the number, identities, and properties of these enzymes are still unknown. Here, we demonstrate that isolated mitochondria from rat brain cortex, incubated in the absence of respiratory substrates, release a Ca²⁺-dependent PLA₂ having biochemical properties characteristic to secreted PLA₂ (sPLA₂) and immunoreacting with the antibody raised against recombinant type IIA sPLA₂ (sPLA₂-IIA). Under identical conditions, no release of fumarase in the extramitochondrial medium was observed. The release of sPLA₂ from mitochondria decreases when mitochondria are incubated in the presence of respiratory substrates such as ADP, malate, and pyruvate, which causes an increase of transmembrane potential determined by cytofluorimetric analysis using DiOC₆(3) as a probe. The treatment of mitochondria with the uncoupler carbonyl cyanide 3-chlorophenylhydrazone slightly enhances sPLA₂ release. The increase of sPLA₂ specific activity after removal of mitochondrial outer membrane indicates that the enzyme is associated with mitoplasts. The mitochondrial localization of the enzyme has been confirmed by electron microscopy in U-251 astrocytoma cells and by confocal laser microscopy in the same cells and in PC-12 cells, where the structurally similar isoform type V-sPLA₂ has mainly nuclear localization. In addition to sPLA₂, mitochondria contain another phospholipase A₂ that is Ca²⁺-independent and sensitive to bromoenol lactone, associated with the outer mitochondrial membrane. We hypothesize that, under reduced respiratory rate, brain mitochondria release sPLA₂-IIA that might contribute to cell damage.

Received for publication, April 14, 2003 , and in revised form, May 14, 2004.

^* This work was supported by Grant 9905238957 from Ministero della Ricerca Scientifica e Tecnologica (to G. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Department of Internal Medicine, Division of Biochemistry, Via del Giochetto, I-06125 Perugia, Italy. Tel.: 39-075-585-7420, Fax: 39-075-585-7420 or 7428; E-mail: goracci{at}unipg.it.

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