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J. Biol. Chem., Vol. 279, Issue 48, 50420-50428, November 26, 2004

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Cytochrome bc₁ Regulates the Mitochondrial Permeability Transition by Two Distinct Pathways^*

Jeffrey S. Armstrong, Hongyuan Yang, Wei Duan, and Matthew Whiteman

From the Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore

The mitochondrial permeability transition (MPT) pore is a calcium-sensitive channel in the mitochondrial inner membrane that plays a crucial role in cell death. Here we show that cytochrome bc₁ regulates the MPT in isolated rat liver mitochondria and in CEM and HL60 cells by two independent pathways. Glutathione depletion activated the MPT via increased production of reactive oxygen species (ROS) generated by cytochrome bc₁. The ROS producing mechanism in cytochrome bc₁ involves movement of the "Rieske" iron-sulfur protein subunit of the enzyme complex, because inhibition of cytochrome bc₁ by pharmacologically blocking iron-sulfur protein movement completely abolished ROS production, MPT activation, and cell death. The classical inhibitor of the MPT, cyclosporine A, had no protective effect against MPT activation. In contrast, the calcium-activated, cyclosporine A-regulated MPT in rat liver mitochondria was also blocked with inhibitors of cytochrome bc₁. These results indicate that electron flux through cytochrome bc₁ regulates two distinct pathways to the MPT, one unregulated and involving mitochondrial ROS and the other regulated and activated by calcium.

Received for publication, August 4, 2004

^* This work was supported by Academic Research Fund Grant R183000103112 (to J. S. A.), National Medical Research Council Grants NMRC/0474/2000, NMRC/0481/2000, and NMRC/0635/2002 (to M. W.), and National of University Singapore Office of Life Science Grant R183000603712 (to M. W.). 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, National University of Singapore, Kent Road, Singapore, 117597, Singapore. Tel.: 65-6874-5996; Fax: 65-6779-1453; E-mail: bchjsa{at}nus.edu.sg.

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