Cyclophilin-D promotes the mitochondrial permeability transition but has opposite effects on apoptosis and necrosis

• Published in: Biochemical journal Vol. 383; no. Pt 1; pp. 101 - 109
• Main Authors: Li, Yanmin, Johnson, Nicholas, Capano, Michela, Edwards, Mina, Crompton, Martin
• Format: Journal Article
• Language: English
• Published: England Portland Press Ltd 01-10-2004
• Subjects: Amino Acid Sequence; Animals; Apoptosis - physiology; Caspases - metabolism; Cell Line; Cyclophilins - biosynthesis; Cyclophilins - physiology; Cyclosporine - pharmacology; Fluorescent Dyes; Intracellular Membranes - metabolism; Ion Channels - physiology; Mitochondria - physiology; Mitochondrial ADP, ATP Translocases - metabolism; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Molecular Sequence Data; Necrosis - metabolism; Onium Compounds - metabolism; Organometallic Compounds; Organophosphorus Compounds - metabolism; Peptidyl-Prolyl Isomerase F; Permeability; Rats; Recombinant Proteins - biosynthesis
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/bj20040669

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.