Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death

Nature. 2005 Mar 31;434(7033):652-8. doi: 10.1038/nature03317.

Abstract

Mitochondria play an important role in energy production, Ca2+ homeostasis and cell death. In recent years, the role of the mitochondria in apoptotic and necrotic cell death has attracted much attention. In apoptosis and necrosis, the mitochondrial permeability transition (mPT), which leads to disruption of the mitochondrial membranes and mitochondrial dysfunction, is considered to be one of the key events, although its exact role in cell death remains elusive. We therefore created mice lacking cyclophilin D (CypD), a protein considered to be involved in the mPT, to analyse its role in cell death. CypD-deficient mice were developmentally normal and showed no apparent anomalies, but CypD-deficient mitochondria did not undergo the cyclosporin A-sensitive mPT. CypD-deficient cells died normally in response to various apoptotic stimuli, but showed resistance to necrotic cell death induced by reactive oxygen species and Ca2+ overload. In addition, CypD-deficient mice showed a high level of resistance to ischaemia/reperfusion-induced cardiac injury. Our results indicate that the CypD-dependent mPT regulates some forms of necrotic death, but not apoptotic death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Calcium / metabolism
  • Calcium / pharmacology
  • Caspases / metabolism
  • Cells, Cultured
  • Cyclophilin D
  • Cyclophilins / deficiency
  • Cyclophilins / genetics
  • Cyclophilins / metabolism*
  • Enzyme Activation / drug effects
  • Fibroblasts / cytology
  • Fibroblasts / pathology
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Hydrogen Peroxide / pharmacology
  • Mice
  • Mice, Knockout
  • Mitochondria, Liver / genetics
  • Mitochondria, Liver / metabolism*
  • Mitochondria, Liver / pathology
  • Mitochondrial Swelling / physiology
  • Myocardial Ischemia / genetics
  • Myocardial Ischemia / metabolism
  • Myocardial Ischemia / pathology
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / pathology
  • Necrosis*
  • Reactive Oxygen Species / metabolism
  • Reactive Oxygen Species / pharmacology
  • Thymus Gland / cytology
  • Thymus Gland / pathology

Substances

  • Cyclophilin D
  • PPIF protein, mouse
  • Reactive Oxygen Species
  • Hydrogen Peroxide
  • Caspases
  • Cyclophilins
  • Calcium