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 and Yoshihide Tsujimoto ()
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Takashi Nakagawa: Laboratory of Molecular Genetics
Shigeomi Shimizu: Laboratory of Molecular Genetics
Tetsuya Watanabe: Osaka University Medical school
Osamu Yamaguchi: Osaka University Medical school
Kinya Otsu: Osaka University Medical school
Hirotaka Yamagata: Laboratory of Molecular Genetics
Hidenori Inohara: Department of Otolaryngology and Sensory Organ Surgery
Takeshi Kubo: Department of Otolaryngology and Sensory Organ Surgery
Yoshihide Tsujimoto: Laboratory of Molecular Genetics

Nature, 2005, vol. 434, issue 7033, 652-658

Abstract: 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 attention1,2. 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.

Date: 2005
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DOI: 10.1038/nature03317

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