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Chemical modification of the mitochondrial permeability transition pore by specific amino acid reagents
Author(s) -
Bernardi Paolo,
Colonna Raffaele,
Costantini Paola,
Eriksson Ove,
Nicolli Annamaria,
Petronilli Valeria,
Scorrano Luca
Publication year - 1999
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199901)46:1<14::aid-ddr3>3.0.co;2-l
Subject(s) - mitochondrial permeability transition pore , chemistry , cyclophilin , mitochondrial membrane transport protein , inner mitochondrial membrane , mitochondrion , biophysics , chemical biology , membrane permeability , drug discovery , reagent , biochemistry , programmed cell death , membrane , biology , apoptosis , gene
Mitochondria of higher cells contain a channel, the permeability transition pore (PTP), that, when open, increases the permeability of the inner membrane to ions and small molecules. The PTP may be of importance in cellular calcium homeostasis and in the execution of programmed cell death, and the definition of the molecular structure of the PTP is, therefore, an urgent problem in cell biology. Because there has been so little structural information to rely on, theories on the nature of the PTP have been unconstrained and ideas have ranged from degradation of membrane phospholipids to cross‐linking of known carrier proteins. The discovery of the high‐affinity inhibitor cyclosporin A (CsA) allowed a clear pharmacologic definition of the PTP, and paved the way to purification of cyclophilin D (CyP‐D), a matrix peptidyl prolyl cis‐trans isomerase that seems to mediate PTP inhibition by CsA. CyP‐D is a soluble protein, however, and the nature of the ion‐conducting channel remains undefined. Here, we review the information provided by the strategy of site‐selective modification of the PTP with specific chemical reagents. Drug Dev. Res. 46:14–17, 1999. © 1999 Wiley‐Liss, Inc.