Document Detail

Mitochondrial targeted cyclophilin D protects cells from cell death by peptidyl prolyl isomerization.
MedLine Citation:
PMID:  12077116     Owner:  NLM     Status:  MEDLINE    
Cyclophilin D (CyPD) is thought to sensitize opening of the mitochondrial permeability transition pore (mPTP) based on the findings that cyclosporin A (CsA), a pseudo-CyPD substrate, hyperpolarizes the mitochondrial membrane potential (DeltaPsi) and inhibits apoptosis. We provide evidence that contrasts with this model. Using live cell imaging and two photon microscopy, we report that overexpression of CyPD desensitizes HEK293 and rat glioma C6 cells to apoptotic stimuli. By site-directed mutagenesis of CyPD that compromises peptidyl-prolyl cis-trans isomerase (PPIase) activity, we demonstrate that the mechanism involved in this protective effect requires PPIase activity. Furthermore, we show that, under resting conditions, DeltaPsi is hyperpolarized in CyPD wild type-overexpressing cells but not in cells overexpressing mutant forms of CyPD that lack PPIase activity. Finally, in glutathione S-transferase (GST) pull-down assays, we demonstrate that CyPD binding to the adenine nucleotide translocator (ANT), which is considered to be the core component of the mPTP, is not affected by the loss of PPIase activity. Collectively, our data suggest that CyPD should be viewed as a cell survival-signaling molecule and indicate a protective role of CyPD against apoptosis that is mediated by one or more targets other than the ANT.
Da-Ting Lin; James D Lechleiter
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2002-06-19
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  277     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2002 Aug 
Date Detail:
Created Date:  2002-08-19     Completed Date:  2002-09-23     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  31134-41     Citation Subset:  IM    
Department of Cellular and Structural Biology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
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MeSH Terms
Binding Sites
Cyclophilins / physiology*
Cyclosporine / pharmacology
Ion Channels / physiology*
Membrane Potentials / drug effects
Mitochondrial ADP, ATP Translocases / metabolism
Mitochondrial Membrane Transport Proteins
Oxidative Stress
Peptidylprolyl Isomerase / physiology*
Staurosporine / pharmacology
tert-Butylhydroperoxide / pharmacology
Grant Support
Reg. No./Substance:
0/Ion Channels; 0/Mitochondrial Membrane Transport Proteins; 0/mitochondrial permeability transition pore; 59865-13-3/Cyclosporine; 62996-74-1/Staurosporine; 75-91-2/tert-Butylhydroperoxide; 9068-80-8/Mitochondrial ADP, ATP Translocases; EC 5.2.1.-/Cyclophilins; EC Isomerase; EC D

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