title: Antamanide, a derivative of Amanita phalloides, is a novel inhibitor of the mitochondrial permeability transition pore.
abstract: Antamanide is a cyclic decapeptide derived from the fungus Amanita phalloides. Here we show that antamanide inhibits the mitochondrial permeability transition pore, a central effector of cell death induction, by targeting the pore regulator cyclophilin D. Indeed, (i) permeability transition pore inhibition by antamanide is not additive with the cyclophilin D-binding drug cyclosporin A, (ii) the inhibitory action of antamanide on the pore requires phosphate, as previously shown for cyclosporin A; (iii) antamanide is ineffective in mitochondria or cells derived from cyclophilin D null animals, and (iv) abolishes CyP-D peptidyl-prolyl cis-trans isomerase activity. Permeability transition pore inhibition by antamanide needs two critical residues in the peptide ring, Phe6 and Phe9, and is additive with ubiquinone 0, which acts on the pore in a cyclophilin D-independent fashion. Antamanide also abrogates mitochondrial depolarization and the ensuing cell death caused by two well-characterized pore inducers, clotrimazole and a hexokinase II N-terminal peptide. Our findings have implications for the comprehension of cyclophilin D activity on the permeability transition pore and for the development of novel pore-targeting drugs exploitable as cell death inhibitors.
authors.affiliation: Department of Biomedical Sciences University of Padova and CNR Institute of Neuroscience, Padova, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Azzolin
authors.forename: Nicola
authors.initials: N
authors.lastname: Antolini
authors.forename: Andrea
authors.initials: A
authors.lastname: Calderan
authors.forename: Paolo
authors.initials: P
authors.lastname: Ruzza
authors.forename: Marco
authors.initials: M
authors.lastname: Sciacovelli
authors.forename: Oriano
authors.initials: O
authors.lastname: Marin
authors.forename: Stefano
authors.initials: S
authors.lastname: Mammi
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.forename: Andrea
authors.initials: A
authors.lastname: Rasola
mesh_terms: D000545:Amanita / Q000737:chemistry; D000818:Animals; D016923:Cell Death; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors*; D003524:Cyclosporins / Q000494:pharmacology; D004347:Drug Interactions; D051379:Mice; D008810:Mice, Inbred C57BL; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D000083162:Mitochondrial Permeability Transition Pore; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010710:Phosphates; D019745:cis-trans-Isomerases / Q000037:antagonists & inhibitors
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D003524:Cyclosporins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D010456:Peptides, Cyclic; D010710:Phosphates; C100265:antamanide; C050026:cyclosporin D; D019745:cis-trans-Isomerases; D021983:Cyclophilins