Cyclophilin-D promotes the mitochondrial permeability transition but has opposite effects on apoptosis and necrosis.
Cyclophilin-D is a peptidylprolyl cis-trans isomerase of the mitochondrial matrix. It is involved in mitochondrial permeability transition, in which the adenine nucleotide translocase of the inner membrane is transformed from an antiporter to a non-selective pore. The permeability transition has been widely considered as a mechanism in both apoptosis and necrosis. The present study examines the effects of cyclophilin-D on the permeability transition and lethal cell injury, using a neuronal (B50) cell line stably overexpressing cyclophilin-D in mitochondria. Cyclophilin-D overexpression rendered isolated mitochondria far more susceptible to the permeability transition induced by Ca2+ and oxidative stress. Similarly, cyclophilin-D overexpression brought forward the onset of the permeability transition in intact cells subjected to oxidative stress. In addition, in the absence of stress, the mitochondria of cells overexpressing cyclophilin-D maintained a lower inner-membrane potential than those of normal cells. All these effects of cyclophilin-D overexpression were abolished by cyclosporin A. It is concluded that cyclophilin-D promotes the permeability transition in B50 cells. However, cyclophilin-D overexpression had opposite effects on apoptosis and necrosis; whereas NO-induced necrosis was promoted, NO- and staurosporine-induced apoptosis were inhibited. These findings indicate that the permeability transition leads to cell necrosis, but argue against its involvement in apoptosis.
Li
Yanmin
Y
Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK.
Johnson
Nicholas
N
Capano
Michela
M
Edwards
Mina
M
Crompton
Martin
M
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000096:biosynthesis / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology; D005456:Fluorescent Dyes; D007425:Intracellular Membranes / Q000378:metabolism; D007473:Ion Channels / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology*; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D008969:Molecular Sequence Data; D009336:Necrosis / Q000378:metabolism*; D009861:Onium Compounds / Q000378:metabolism; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds / Q000378:metabolism; D010539:Permeability; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis
D000081406:Peptidyl-Prolyl Isomerase F; D005456:Fluorescent Dyes; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009861:Onium Compounds; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D011994:Recombinant Proteins; C110932:tetramethyl rhodamine ethyl ester; D016572:Cyclosporine; D000226:Mitochondrial ADP, ATP Translocases; D020169:Caspases; D021983:Cyclophilins; C013289:tetraphenylphosphonium