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Nature 434, 658-662 (31 March 2005) | doi:10.1038/nature03434; Received 4 November 2004; Accepted 7 February 2005
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Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death
Christopher P. Baines1, Robert A. Kaiser1, Nicole H. Purcell1, N. Scott Blair1, Hanna Osinska1, Michael A. Hambleton2, Eric W. Brunskill3, M. Richard Sayen4, Roberta A. Gottlieb4, Gerald W. Dorn, II3, Jeffrey Robbins1 & Jeffery D. Molkentin1
- Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA
- Department of Molecular Genetics, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA
- Department of Medicine, University of Cincinnati, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA
Correspondence to: Jeffery D. Molkentin1 Correspondence and requests for materials should be addressed to J.D.M. (Email: jeff.molkentin@cchmc.org).
Abstract
Mitochondria play a critical role in mediating both apoptotic and necrotic cell death. The mitochondrial permeability transition (mPT) leads to mitochondrial swelling, outer membrane rupture and the release of apoptotic mediators. The mPT pore is thought to consist of the adenine nucleotide translocator, a voltage-dependent anion channel, and cyclophilin D (the Ppif gene product), a prolyl isomerase located within the mitochondrial matrix1, 2. Here we generated mice lacking Ppif and mice overexpressing cyclophilin D in the heart. Ppif null mice are protected from ischaemia/reperfusion-induced cell death in vivo, whereas cyclophilin D-overexpressing mice show mitochondrial swelling and spontaneous cell death. Mitochondria isolated from the livers, hearts and brains of Ppif null mice are resistant to mitochondrial swelling and permeability transition in vitro. Moreover, primary hepatocytes and fibroblasts isolated from Ppif null mice are largely protected from Ca2+-overload and oxidative stress-induced cell death. However, Bcl-2 family member-induced cell death does not depend on cyclophilin D, and Ppif null fibroblasts are not protected from staurosporine or tumour-necrosis factor-
-induced death. Thus, cyclophilin D and the mitochondrial permeability transition are required for mediating Ca2+- and oxidative damage-induced cell death, but not Bcl-2 family member-regulated death.
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