title: Modulation of the mitochondrial permeability transition by cyclophilin D: moving closer to F(0)-F(1) ATP synthase?
abstract: Cyclophilin D was recently shown to mask an inhibitory site of the mitochondrial permeability transition pore (PTP) for phosphate, and to constitutively bind F(0)-F(1) ATP synthase resulting in the slowing of ATP synthesis and hydrolysis rates, thus regulating matrix adenine nucleotide levels. Here we review the striking similarities of the factors affecting the threshold for PTP induction, to those affecting binding of phosphate to formerly proposed sides on F(1)-ATPase affecting ATP hydrolytic activity, including critical arginine residues, matrix pH, [Mg(2+)], adenine nucleotides and proton motive force. Based on these similarities, we scrutinize the hypothesis that in depolarized mitochondria exhibiting reversal of F(0)-F(1) ATP synthase operation, the genetic ablation of cyclophilin D or its inhibition by cyclosporin A results in accelerated proton pumping by ATP hydrolysis, opposing a further decrease in membrane potential and promoting high matrix phosphate levels, both negatively affecting the probability of PTP opening.
authors.affiliation: Department of Medical Biochemistry, Semmelweis University, Budapest 1094, Hungary.
authors.forename: Christos
authors.initials: C
authors.lastname: Chinopoulos
authors.forename: Vera
authors.initials: V
authors.lastname: Adam-Vizi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism*; D016572:Cyclosporine / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008928:Mitochondria / Q000187:drug effects*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D010539:Permeability / Q000187:drug effects*; D006180:Proton-Translocating ATPases / Q000378:metabolism
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D006180:Proton-Translocating ATPases; D021983:Cyclophilins