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

Biochem J. 2004 Oct 1;383(Pt 1):101-9. doi: 10.1042/BJ20040669.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / physiology*
  • Caspases / metabolism
  • Cell Line
  • Cyclophilin D
  • 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
  • Permeability
  • Rats
  • Recombinant Proteins / biosynthesis

Substances

  • Cyclophilin D
  • Fluorescent Dyes
  • Ion Channels
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Onium Compounds
  • Organometallic Compounds
  • Organophosphorus Compounds
  • Recombinant Proteins
  • tetramethyl rhodamine ethyl ester
  • Cyclosporine
  • Mitochondrial ADP, ATP Translocases
  • Caspases
  • Cyclophilins
  • tetraphenylphosphonium