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J. Biol. Chem., Vol. 279, Issue 51, 53103-53108, December 17, 2004

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Ca²+-induced Reactive Oxygen Species Production Promotes Cytochrome c Release from Rat Liver Mitochondria via Mitochondrial Permeability Transition (MPT)-dependent and MPT-independent Mechanisms

ROLE OF CARDIOLIPIN^*

Giuseppe Petrosillo, Francesca M. Ruggiero, Marilva Pistolese, and Giuseppe Paradies

From the Department of Biochemistry and Molecular Biology and Consiglio Nazionale delle Ricerche Institute of Biomembranes and Bioenergetics, University of Bari, 70126 Bari, Italy

Release of cytochrome c from mitochondria is considered a critical, early event in the induction of an apoptosis cascade that ultimately leads to programmed cell death. Mitochondrial Ca²⁺ loading is a trigger for the release of cytochrome c, although the molecular mechanism underlying this effect is not fully clarified. This study tested the hypothesis that distinct Ca²⁺ thresholds may induce cytochrome c release from rat liver mitochondria by membrane permeability transition (MPT)-dependent and independent mechanisms. The involvement of reactive oxygen species (ROS) and cardiolipin in the Ca²⁺-induced cytochrome c release was also investigated. Cytochrome c was quantitated by a new, very sensitive, and rapid reverse-phase high performance liquid chromatography method with a detection limit of 0.1 pmol/sample. We found that a low extramitochondrial Ca²⁺ level (2 µM) promoted the release of 13% of the total alamethicin releasable pool of cytochrome c from mitochondria. This release was not depending of MPT; it was mediated by Ca²⁺-induced ROS production and cardiolipin peroxidation and appears to involve the voltage-dependent anion channel. High extramitochondrial Ca²⁺ level (20 µM) promoted 45% of the total releasable pool of cytochrome c. This process was MPT-dependent and was also mediated by ROS and cardiolipin. It is suggested that distinct Ca²⁺ levels may determine the mode and the amount of cytochrome c release from rat liver mitochondria. The data may help to clarify the molecular mechanism underlying the Ca²⁺-induced release of cytochrome c from rat liver mitochondria and the role played by ROS and cardiolipin in this process.

Received for publication, July 6, 2004 , and in revised form, September 29, 2004.

^* This work was supported by a grant from the National Research Project (PRIN) "Bioenergetics and Membrane Transport" Ministero Università Ricera Scientifica Techologica, Italy, 2003–2005. 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: Dept. of Biochemistry and Molecular Biology, University of Bari, Via E. Orabona, 4, 70126 Bari, Italy. Tel.: 39-80-5443324; Fax: 39-80-5443317; E-mail: g.paradies{at}biologia.uniba.it.

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