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


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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  1. Tsujimoto, Y. Cell death regulation by the Bcl-2 protein family in the mitochondria. J. Cell. Physiol. 195, 158–167 (2003)

    Article  CAS  Google Scholar 

  2. Green, D. R. & Kroemer, G. The pathophysiology of mitochondrial cell death. Science 305, 626–629 (2004)

    Article  ADS  CAS  Google Scholar 

  3. Halestrap, A. P., McStay, G. P. & Clarke, S. J. The permeability transition pore complex: another view. Biochimie 84, 153–166 (2002)

    Article  CAS  Google Scholar 

  4. Crompton, M. On the involvement of mitochondrial intermembrane junctional complexes in apoptosis. Curr. Med. Chem. 10, 1473–1484 (2003)

    Article  CAS  Google Scholar 

  5. Kokoszka, J. E. et al. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427, 461–465 (2004)

    Article  ADS  CAS  Google Scholar 

  6. Halestrap, A. P. Mitochondrial permeability: dual role for the ADP/ATP translocator? Nature [online] 430, 983 (2004) (doi:10.1038/nature02816)

    Article  Google Scholar 

  7. Galat, A. & Metcalfe, S. M. Peptidylproline cis/trans isomerases. Prog. Biophys. Mol. Biol. 63, 67–118 (1995)

    Article  CAS  Google Scholar 

  8. Broekemeier, K. M., Dempsey, M. E. & Pfeiffer, D. R. Cyclosporin A is a potent inhibitor of the inner membrane permeability transition in liver mitochondria. J. Biol. Chem. 264, 7826–7830 (1989)

    CAS  PubMed  Google Scholar 

  9. He, L. & Lemasters, J. J. Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function? FEBS Lett. 512, 1–7 (2002)

    Article  ADS  CAS  Google Scholar 

  10. Scorrano, L. et al. A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev. Cell 2, 55–67 (2002)

    Article  CAS  Google Scholar 

  11. Wei, M. C. et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730 (2001)

    Article  ADS  CAS  Google Scholar 

  12. Narita, M. et al. Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria. Proc. Natl Acad. Sci. USA 95, 14681–14686 (1998)

    Article  ADS  CAS  Google Scholar 

  13. Eskes, R. et al. Bax-induced cytochrome C release from mitochondria is independent of the permeability transition pore but highly dependent on Mg2+ ions. J. Cell Biol. 143, 217–224 (1998)

    Article  CAS  Google Scholar 

  14. Finucane, D. M., Bossy-Wetzel, E., Waterhouse, N. J., Cotter, T. G. & Green, D. R. Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL. J. Biol. Chem. 274, 2225–2233 (1999)

    Article  CAS  Google Scholar 

  15. von Ahsen, O. et al. Preservation of mitochondrial structure and function after Bid- or Bax-mediated cytochrome c release. J. Cell Biol. 150, 1027–1036 (2000)

    Article  CAS  Google Scholar 

  16. Trollinger, D. R., Cascio, W. E. & Lemasters, J. J. Selective loading of Rhod 2 into mitochondria shows mitochondrial Ca2+ transients during the contractile cycle in adult rabbit cardiac myocytes. Biochem. Biophys. Res. Commun. 236, 738–742 (1997)

    Article  CAS  Google Scholar 

  17. Weiss, J. N., Korge, P., Honda, H. M. & Ping, P. Role of the mitochondrial permeability transition in myocardial disease. Circ. Res. 93, 292–301 (2003)

    Article  CAS  Google Scholar 

  18. Shimizu, S. et al. Beneficial effects of cyclosporine on reoxygenation injury in hypoxic rat liver. Transplantation 57, 1562–1566 (1994)

    Article  CAS  Google Scholar 

  19. Javadov, S. A. et al. Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart. J. Physiol. (Lond.) 549, 513–524 (2003)

    Article  CAS  Google Scholar 

  20. Matsumoto, S., Friberg, H., Ferrand-Drake, M. & Wieloch, T. Blockade of the mitochondrial permeability transition pore diminishes infarct size in the rat after transient middle cerebral artery occlusion. J. Cereb. Blood Flow Metab. 19, 736–741 (1999)

    Article  CAS  Google Scholar 

  21. Khaspekov, L., Friberg, H., Halestrap, A., Viktorov, I. & Wieloch, T. Cyclosporin A and its nonimmunosuppressive analogue N-Me-Val-4-cyclosporin A mitigate glucose/oxygen deprivation-induced damage to rat cultured hippocampal neurons. Eur. J. Neurosci. 11, 3194–3198 (1999)

    Article  CAS  Google Scholar 

  22. Zamzami, N. & Kroemer, G. The mitochondrion in apoptosis: how Pandora's box opens. Nature Rev. Mol. Cell Biol. 2, 67–71 (2001)

    Article  CAS  Google Scholar 

  23. Li, Y., Johnson, N., Capano, M., Edwards, M. & Crompton, M. Cyclophilin-D promotes the mitochondrial permeability transition but has opposite effects on apoptosis and necrosis. Biochem. J. 383, 101–109 (2004)

    Article  CAS  Google Scholar 

  24. Shimizu, S. et al. Bcl-2 prevents apoptotic mitochondrial dysfunction by regulating proton flux. Proc. Natl Acad. Sci. USA 95, 1455–1459 (1998)

    Article  ADS  CAS  Google Scholar 

  25. Fischer, G., Wittmann-Liebold, B., Lang, K., Kiefhaber, T. & Schmid, F. X. Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature 337, 476–478 (1989)

    Article  ADS  CAS  Google Scholar 

  26. Hatano, E. et al. The mitochondrial permeability transition augments Fas-induced apoptosis in mouse hepatocytes. J. Biol. Chem. 275, 11814–11823 (2000)

    Article  CAS  Google Scholar 

  27. Shinzawa, K. & Tsujimoto, Y. PLA2 activity is required for nuclear shrinkage in caspase-independent cell death. J. Cell Biol. 163, 1219–1230 (2003)

    Article  CAS  Google Scholar 

  28. Shimizu, S., Eguchi, Y., Kamiike, W., Matsuda, H. & Tsujimoto, Y. Bcl-2 expression prevents activation of the ICE protease cascade. Oncogene 12, 2251–2257 (1996)

    CAS  PubMed  Google Scholar 

  29. Byrne, A. M., Lemasters, J. J. & Nieminen, A. L. Contribution of increased mitochondrial free Ca2+ to the mitochondrial permeability transition induced by tert-butylhydroperoxide in rat hepatocytes. Hepatology 29, 1523–1531 (1999)

    Article  CAS  Google Scholar 

  30. Yamashita, N. et al. Exercise provides direct biphasic cardioprotection via manganese superoxide dismutase activation. J. Exp. Med. 189, 1699–1706 (1999)

    Article  CAS  Google Scholar 

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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).

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