Journal Article

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

Sayen, M. Richard, Robbins, Jeffrey, Kaiser, Robert A., Molkentin, Jeffery D., Baines, Christopher P., Brunskill, Eric W., Purcell, Nicole H., Hambleton, Michael A., Blair, N. Scott, Gottlieb, Roberta A., Dorn, Gerald W., Osinska, Hanna

2005

Overview

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 1 , 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 Ca 2+ -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 Ca 2+ - and oxidative damage-induced cell death, but not Bcl-2 family member-regulated death.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Adenoviridae - genetics / Ageing, cell death / Animals / Atractyloside - pharmacology / bcl-2-Associated X Protein / BH3 Interacting Domain Death Agonist Protein / Biological and medical sciences / Brain - cytology / Calcium - metabolism / Calcium - pharmacology / Carrier Proteins - metabolism / Caspases - metabolism / Cell cycle / Cell death / Cell Death - drug effects / Cell physiology / Cells, Cultured / Cellular biology / Cyclophilins - deficiency / Cyclophilins - genetics / Cyclophilins - metabolism / Cytochromes c - metabolism / Deoxyribonucleic acid / DNA / Fibroblasts / Fundamental and applied biological sciences. Psychology / Gene Deletion / Humanities and Social Sciences / Hydrogen Peroxide - pharmacology / letter / Liver - cytology / Mice / Mice, Knockout / Mice, Transgenic / Mitochondria - drug effects / Mitochondria - metabolism / Mitochondria - pathology / Mitochondrial DNA / Mitochondrial Swelling - drug effects / Mitochondrial Swelling - physiology / Molecular and cellular biology / Mortality / multidisciplinary / Myocytes, Cardiac - cytology / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - pathology / Oxidative Stress / Peptidyl-Prolyl Isomerase F / Permeability / Proto-Oncogene Proteins c-bcl-2 - genetics / Proto-Oncogene Proteins c-bcl-2 - metabolism / Rodents / Science / Science (multidisciplinary)