Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia.
Mitochondrial permeability transition (PT) is a phenomenon induced by high levels of matrix calcium and is characterized by the opening of the PT pore (PTP). Activation of the PTP results in loss of mitochondrial membrane potential, expansion of the matrix, and rupture of the mitochondrial outer membrane. Consequently, PT has been implicated in both apoptotic and necrotic cell death. Cyclophilin D (CypD) appears to be a critical component of the PTP. To investigate the role of CypD in cell death, we created a CypD-deficient mouse. In vitro, CypD-deficient mitochondria showed an increased capacity to retain calcium and were no longer susceptible to PT induced by the addition of calcium. CypD-deficient primary mouse embryonic fibroblasts (MEFs) were as susceptible to classical apoptotic stimuli as the WT, suggesting that CypD is not a central component of cell death in response to these specific death stimuli. However, CypD-deficient MEFs were significantly less susceptible than their WT counterparts to cell death induced by hydrogen peroxide, implicating CypD in oxidative stress-induced cell death. Importantly, CypD-deficient mice displayed a dramatic reduction in brain infarct size after acute middle cerebral artery occlusion and reperfusion, strongly supporting an essential role for CypD in an ischemic injury model in which calcium overload and oxidative stress have been implicated.
Schinzel
Anna C
AC
Howard Hughes Medical Institute and Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. anna.schinzel@dfci.harvard.edu
Takeuchi
Osamu
O
Huang
Zhihong
Z
Fisher
Jill K
JK
Zhou
Zhipeng
Z
Rubens
Jeffery
J
Hetz
Claudio
C
Danial
Nika N
NN
Moskowitz
Michael A
MA
Korsmeyer
Stanley J
SJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000633:toxicity; D007425:Intracellular Membranes / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D008933:Mitochondrial Swelling / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010539:Permeability; D013053:Spectrophotometry; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism*
D000081406:Peptidyl-Prolyl Isomerase F; C000631446:PPIF protein, mouse; D050994:Voltage-Dependent Anion Channels; D006861:Hydrogen Peroxide; D021983:Cyclophilins; D002118:Calcium