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

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.

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Figure 1: Absence of mPT in CypD-deficient (CypD-/-) mitochondria.
Figure 2: No resistance of Cyp D-/- cells to multiple apoptotic stimuli a, b, Susceptibility of primary thymocytes and MEFs to various apoptotic stimuli.
Figure 3: Resistance of CypD-/- cells to necrosis induced by reactive oxygen species and Ca2+ overload.
Figure 4: Prevention of cardiac ischaemia/reperfusion injury in CypD-/- mice.

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Acknowledgements

We are grateful to K. Tagawa for helpful discussion and C. Thompson for providing Bak-deficient mice. CypD-deficient mice were developed in collaboration with Lexicon Genetics Incorporated. This study was supported in part by a grant for Scientific Research on Priority Areas, a grant for Center of Excellence Research, a grant for the 21st century COE Program, a grant for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan, and by a grant for Research on Dementia and Fracture from the Ministry of Health, Labour and Welfare of Japan.

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Correspondence to Yoshihide Tsujimoto.

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Supplementary information

Supplementary Figure Legends (DOC 22 kb)

Supplementary Figure 1

Creation of Cyp D-deficient Mice. (PDF 2240 kb)

Supplementary Figure 2

No difference in respiration rate between control and Cyp D-deficient mitochondria. (PDF 1047 kb)

Supplementary Figure 3

High doses of Ca2+ cause ΔΨ loss in Cyp D-deficient mitochondria. (PDF 528 kb)

Supplementary Figure 4

Absence of mPT in Cyp D-deficient mitochondria by mPT inducers. (PDF 48 kb)

Supplementary Figure 5

Resistance of ΔΨ loss by Cyp D deficiency. (PDF 429 kb)

Supplementary Table

Analysis of cardiac sizes and functions by echocardiography. (DOC 25 kb)

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Nakagawa, T., Shimizu, S., Watanabe, T. et al. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434, 652–658 (2005). https://doi.org/10.1038/nature03317

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