Cyclophilin D links programmed cell death and organismal aging in Podospora anserina.
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.
Brust
Diana
D
Johann Wolfgang Goethe University, Institute of Molecular Biosciences, Frankfurt, Germany.
Daum
Bertram
B
Breunig
Christine
C
Hamann
Andrea
A
Kühlbrandt
Werner
W
Osiewacz
Heinz D
HD
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
D000081406:Peptidyl-Prolyl Isomerase F; D004791:Enzyme Inhibitors; D016572:Cyclosporine; D021983:Cyclophilins