Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death.
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 matrix. 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-alpha-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.
Baines
Christopher P
CP
Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Kaiser
Robert A
RA
Purcell
Nicole H
NH
Blair
N Scott
NS
Osinska
Hanna
H
Hambleton
Michael A
MA
Brunskill
Eric W
EW
Sayen
M Richard
MR
Gottlieb
Roberta A
RA
Dorn
Gerald W
GW
Robbins
Jeffrey
J
Molkentin
Jeffery D
JD
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001278:Atractyloside / Q000494:pharmacology; D051023:BH3 Interacting Domain Death Agonist Protein; D001921:Brain / Q000166:cytology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D005347:Fibroblasts; D017353:Gene Deletion; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008099:Liver / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008933:Mitochondrial Swelling / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D002352:Carrier Proteins; D000081406:Peptidyl-Prolyl Isomerase F; C000631446:PPIF protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D001278:Atractyloside; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D020169:Caspases; D021983:Cyclophilins; D002118:Calcium