Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia.

Abstract

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.

• Authors: Anna C Schinzel, Osamu Takeuchi, Zhihong Huang, Jill K Fisher, Zhipeng Zhou, Jeffery Rubens, Claudio Hetz, Nika N Danial, Michael A Moskowitz, Stanley J Korsmeyer
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 34 Pg. 12005-10 (Aug 23 2005) ISSN: 0027-8424 [Print] United States
• PMID: 16103352 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cyclophilin D
• PPIF protein, mouse
• Voltage-Dependent Anion Channels
• Hydrogen Peroxide
• Cyclophilins
• Calcium

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Brain Ischemia (metabolism, physiopathology)
• Calcium (metabolism)
• Cyclophilin D
• Cyclophilins (deficiency, metabolism)
• Hydrogen Peroxide (toxicity)
• Intracellular Membranes (metabolism)
• Mice
• Mice, Transgenic
• Microscopy, Electron, Transmission
• Mitochondria (metabolism, ultrastructure)
• Mitochondrial Swelling (physiology)
• Neurons (metabolism, physiology)
• Permeability
• Spectrophotometry
• Voltage-Dependent Anion Channels (metabolism)