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J. Biol. Chem., Vol. 283, Issue 39, 26312-26323, September 26, 2008

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The Mitochondrial Phosphate Carrier Interacts with Cyclophilin D and May Play a Key Role in the Permeability Transition^*

From the Department of Biochemistry and The Bristol Heart Institute, University of Bristol, School of Medical Sciences, University Walk, Bristol BS8 1TD, United Kingdom

The mitochondrial permeability transition pore (MPTP) plays a key role in cell death, yet its molecular identity remains uncertain. Although knock-out studies have confirmed critical roles for both cyclophilin-D (CyP-D) and the adenine nucleotide translocase (ANT), given a strong enough stimulus MPTP opening can occur in the absence of either. Here we provide evidence that the mitochondrial phosphate carrier (PiC) may also be a critical component of the MPTP. Phenylarsine oxide (PAO) was found to activate MPTP opening in the presence of carboxyatractyloside (CAT) that prevents ANT binding to immobilized PAO. Only four proteins from solubilized CAT-treated beef heart inner mitochondrial membranes bound to immobilized PAO, one of which was the PiC. GST-CyP-D pull-down and co-immunoprecipitation studies revealed CsA-sensitive binding of PiC to CyP-D; this increased following diamide treatment. Co-immunoprecipitation of the ANT with the PiC was also observed but was insensitive to CsA treatment. N-ethylmaleimide and ubiquinone analogues (UQ₀ and Ro 68-3400) inhibited phosphate transport into rat liver mitochondria with the same concentration dependence as their inhibition of MPTP opening. UQ₀ and Ro 68-3400 also induced the "m" conformation of the ANT, as does NEM, and reduced the binding of both the PiC and ANT to the PAO column. We propose a model for the MPTP in which a calcium-triggered conformational change of the PiC, facilitated by CyP-D, induces pore opening. An interaction of the PiC with the ANT may enable agents that bind to either transporter to modulate pore opening.

Received for publication, July 9, 2008

^* This work was supported in part by a Research Studentship (FS/04/043) from the British Heart Foundation (to A. W. C. L.) and Programme Grant support (RG/03/002). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and Table S1.

¹ Supported by a University of Bristol for a postgraduate scholarship and an Overseas Research Scholarship award.

² To whom correspondence should be addressed: Dept. of Biochemistry, University of Bristol, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK. Tel.: 44-117-3312118; Fax: 44-117-3312168; E-mail: a.halestrap{at}bristol.ac.uk.

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