TSUJIMOTO Yoshihide ≪Molecular Genetics≫ TAKEDA Junji ≪Environmental and Molecular Medicine≫ “Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic death”
Publish Nature 434: 652-658 (2005)
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 apoptotic and necrotic death, the mitochondrial permeability transition (mPT), which leads to disruption of the outer mitochondrial membrane and mitochondrial dysfunction, is considered to be one of the key events, although its exact role in cell death remains elusive. Therefore, we created mice lacking cyclophilin D (Cyp D), which is considered to be involved in the mPT to analyze its role in cell death. Cyp D-deficient mice were developmentally normal and showed no apparent anomalies, but Cyp D-deficient mitochondria did not undergo the Cyclosporin A (CsA)-sensitive mPT. Cyp D-deficient cells died normally in response to various apoptotic stimuli, but showed resistance to necrotic cell death induced by oxygen radicals and Ca2+ overload. In addition, Cyp D-deficient mice showed a high level of resistance to ischemia/ reperfusion-induced cardiac injury. Our results indicate that the Cyp D-dependent mPT regulates some forms of necrotic death, but not apoptotic death.