title: Mitochondrial Thioredoxin System as a Modulator of Cyclophilin D Redox State.
abstract: The mitochondrial thioredoxin system (NADPH, thioredoxin reductase, thioredoxin) is a major redox regulator. Here we have investigated the redox correlation between this system and the mitochondrial enzyme cyclophilin D. The peptidyl prolyl cis-trans isomerase activity of cyclophilin D was stimulated by the thioredoxin system, while it was decreased by cyclosporin A and the thioredoxin reductase inhibitor auranofin. The redox state of cyclophilin D, thioredoxin 1 and 2 and peroxiredoxin 3 was measured in isolated rat heart mitochondria and in tumor cell lines (CEM-R and HeLa) by redox Western blot analysis upon inhibition of thioredoxin reductase with auranofin, arsenic trioxide, 1-chloro-2,4-dinitrobenzene or after treatment with hydrogen peroxide. A concomitant oxidation of thioredoxin, peroxiredoxin and cyclophilin D was observed, suggesting a redox communication between the thioredoxin system and cyclophilin. This correlation was further confirmed by i) co-immunoprecipitation assay of cyclophilin D with thioredoxin 2 and peroxiredoxin 3, ii) molecular modeling and iii) depleting thioredoxin reductase by siRNA. We conclude that the mitochondrial thioredoxin system controls the redox state of cyclophilin D which, in turn, may act as a regulator of several processes including ROS production and pro-apoptotic factors release.
authors.affiliation: Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/b, 35131 Padova, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Folda
authors.affiliation: Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/b, 35131 Padova, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Citta
authors.affiliation: Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/b, 35131 Padova, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Scalcon
authors.affiliation: Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/b, 35131 Padova, Italy.
authors.forename: Tito
authors.initials: T
authors.lastname: Calì
authors.affiliation: Shangai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, No. 99 Haike Road, Pudong, Shanghai 201210, China.
authors.forename: Francesco
authors.initials: F
authors.lastname: Zonta
authors.affiliation: Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/b, 35131 Padova, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Scutari
authors.affiliation: Institute of Neuroscience (CNR), viale G. Colombo 3, 35131 Padova, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bindoli
authors.affiliation: Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/b, 35131 Padova, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rigobello
mesh_terms: D000818:Animals; D001310:Auranofin / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D016877:Oxidants / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D061105:Peroxiredoxin III / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D000072417:Protein Domains; D034622:RNA Interference; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D054482:Thioredoxin Reductase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D016877:Oxidants; D017382:Reactive Oxygen Species; D001310:Auranofin; D013879:Thioredoxins; D016572:Cyclosporine; D006861:Hydrogen Peroxide; D061105:Peroxiredoxin III; D054482:Thioredoxin Reductase 2; D021983:Cyclophilins