Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death

Christopher P. Baines, Robert A. Kaiser, Nicole H. Purcell, N. Scott Blair, Hanna Osinska, Michael A. Hambleton, Eric W. Brunskill, M. Richard Sayen, Roberta A. Gottlieb, Gerald W. Dorn, Jeffrey Robbins and Jeffery D. Molkentin ()
Additional contact information
Christopher P. Baines: Children's Hospital Medical Center
Robert A. Kaiser: Children's Hospital Medical Center
Nicole H. Purcell: Children's Hospital Medical Center
N. Scott Blair: Children's Hospital Medical Center
Hanna Osinska: Children's Hospital Medical Center
Michael A. Hambleton: Children's Hospital Medical Center
Eric W. Brunskill: University of Cincinnati, Children's Hospital Medical Center
M. Richard Sayen: The Scripps Research Institute
Roberta A. Gottlieb: The Scripps Research Institute
Gerald W. Dorn: University of Cincinnati, Children's Hospital Medical Center
Jeffrey Robbins: Children's Hospital Medical Center
Jeffery D. Molkentin: Children's Hospital Medical Center

Nature, 2005, vol. 434, issue 7033, 658-662

Abstract: 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-α-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.

Date: 2005
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DOI: 10.1038/nature03434

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