title: Cyclophilin D links programmed cell death and organismal aging in Podospora anserina.
abstract: Cyclophilin D (CYPD) is a mitochondrial peptidyl prolyl-cis,trans-isomerase involved in opening of the mitochondrial permeability transition pore (mPTP). CYPD abundance increases during aging in mammalian tissues and in the aging model organism Podospora anserina. Here, we show that treatment of the P. anserina wild-type with low concentrations of the cyclophilin inhibitor cyclosporin A (CSA) extends lifespan. Transgenic strains overexpressing PaCypD are characterized by reduced stress tolerance, suffer from pronounced mitochondrial dysfunction and are characterized by accelerated aging and induction of cell death. Treatment with CSA leads to correction of mitochondrial function and lifespan to that of the wild-type. In contrast, PaCypD deletion strains are not affected by CSA within the investigated concentration range and show increased resistance against inducers of oxidative stress and cell death. Our data provide a mechanistic link between programmed cell death (PCD) and organismal aging and bear implications for the potential use of CSA to intervene into biologic aging.
authors.affiliation: Johann Wolfgang Goethe University, Institute of Molecular Biosciences, Frankfurt, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Brust
authors.forename: Bertram
authors.initials: B
authors.lastname: Daum
authors.forename: Christine
authors.initials: C
authors.lastname: Breunig
authors.forename: Andrea
authors.initials: A
authors.lastname: Hamann
authors.forename: Werner
authors.initials: W
authors.lastname: Kühlbrandt
authors.forename: Heinz D
authors.initials: HD
authors.lastname: Osiewacz
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D048468:Podospora / Q000166:cytology* / Q000254:growth & development*; D013329:Structure-Activity Relationship
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D004791:Enzyme Inhibitors; D016572:Cyclosporine; D021983:Cyclophilins