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Recent progress on regulation of the mitochondrial permeability transition pore; a cyclosporin-sensitive pore in the inner mitochondrial membrane

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Abstract

The mitochondrial permeability transition pore allows solutes with a m.w. ≲1500 to equilibrate across the inner membrane. A closed pore is favored by cyclosporin A acting at a high-affinity site, which may be the matrix space cylophilin isozyme. Early results obtained with cyclosporin A analogs and metabolites support this hypothesis. Inhibition by cyclosporin does not appear to require inhibition of calcineurin activity; however, it may relate to inhibition of cyclophilin peptide bond isomerase activity. The permeability transition pore is strongly regulated by both the membrane potential (Δψ) and ΔpH components of the mitochondrial protonmotive force. A voltage sensor which is influenced by the disulfide/sulhydryl state of vicinal sulfhydryls is proposed to render pore opening sensitive to Δψ. Early results indicate that this sensor is also responsive to membrane surface potential and/or to surface potential gradients. Histidine residues located on the matrix side of the inner membrane render the pore responsive to ΔpH. The pore is also regulated by several ions and metabolites which act at sites that are interactive. There are many analogies between the systems which regulate the permeability transition pore and the NMDA receptor channel. These suggest structural similarities and that the permeability transition pore belongs to the family of ligand gated ion channels.

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Authors and Affiliations

  1. From the Department of Medical Biochemistry, The Ohio State University, 43210, Columbus, Ohio

    Kimberly M. Broekemeier & Douglas R. Pfeiffer

  2. CNR Mitochondrial Physiology Unit and Department of Biomedical Sciences, University of Padova, I-35121, Padova, Italy

    Paolo Bernardi

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  1. Paolo Bernardi
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  2. Kimberly M. Broekemeier
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  3. Douglas R. Pfeiffer
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Bernardi, P., Broekemeier, K.M. & Pfeiffer, D.R. Recent progress on regulation of the mitochondrial permeability transition pore; a cyclosporin-sensitive pore in the inner mitochondrial membrane. J Bioenerg Biomembr 26, 509–517 (1994). https://doi.org/10.1007/BF00762735

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