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

Takashi Nakagawa, Shigeomi Shimizu, Tetsuya Watanabe, Osamu Yamaguchi, Kinya Otsu, Hirotaka Yamagata, Hidenori Inohara, Takeshi Kubo, Yoshihide Tsujimoto*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1431 Scopus citations

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.

Original languageEnglish
Pages (from-to)652-658
Number of pages7
JournalNature
Volume434
Issue number7033
DOIs
StatePublished - 2005/03/31

ASJC Scopus subject areas

  • General

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