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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Halestrap, Andrew P. Leung, Anna W. C. Varanyuwatana, Pinadda |
| Description | Author Affiliation: Leung AW ( Department of Biochemistry and The Bristol Heart Institute, University of Bristol, School of Medical Sciences, University Walk, Bristol BS8 1TD, United Kingdom.) |
| Abstract | 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 (UQ(0) and Ro 68-3400) inhibited phosphate transport into rat liver mitochondria with the same concentration dependence as their inhibition of MPTP opening. UQ(0) 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. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 39 |
| Volume Number | 283 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2008-09-26 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cell Membrane Permeability Physiology Cyclophilins Metabolism Mitochondria, Heart Mitochondria, Liver Mitochondrial Membranes Mitochondrial Proteins Phosphate Transport Proteins Animals Arsenicals Pharmacology Benzoquinones Drug Effects Antagonists & Inhibitors Cyclosporine Dibenzocycloheptenes Enzyme Inhibitors Ethylmaleimide Ion Transport Mitochondrial ADP, ATP Translocases Protein Binding Protein Conformation Spiro Compounds Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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