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Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death.
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MedLine Citation:
PMID:  7629499     Owner:  NLM     Status:  MEDLINE    
Programmed cell death (PCD) is a physiological process commonly defined by alterations in nuclear morphology (apoptosis) and/or characteristic stepwise degradation of chromosomal DNA occurring before cytolysis. However, determined characteristics of PCD such as loss in mitochondrial reductase activity or cytolysis can be induced in enucleated cells, indicating cytoplasmic PCD control. Here we report a sequential disregulation of mitochondrial function that precedes cell shrinkage and nuclear fragmentation. A first cyclosporin A-inhibitable step of ongoing PCD is characterized by a reduction of mitochondrial transmembrane potential, as determined by specific fluorochromes (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine++ + iodide; 3,3'dihexyloxacarbocyanine iodide). Cytofluorometrically purified cells with reduced mitochondrial transmembrane potential are initially incapable of oxidizing hydroethidine (HE) into ethidium. Upon short-term in vitro culture, such cells acquire the capacity of HE oxidation, thus revealing a second step of PCD marked by mitochondrial generation of reactive oxygen species (ROS). This step can be selectively inhibited by rotenone and ruthenium red yet is not affected by cyclosporin A. Finally, cells reduce their volume, a step that is delayed by radical scavengers, indicating the implication of ROS in the apoptotic process. This sequence of alterations accompanying early PCD is found in very different models of apoptosis induction: glucocorticoid-induced death of lymphocytes, activation-induced PCD of T cell hybridomas, and tumor necrosis factor-induced death of U937 cells. Transfection with the antiapoptotic protooncogene Bcl-2 simultaneously inhibits mitochondrial alterations and apoptotic cell death triggered by steroids or ceramide. In vivo injection of fluorochromes such as 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide; 3,3'dihexyloxacarbocyanine iodide; or HE allows for the detection of cells that are programmed for death but still lack nuclear DNA fragmentation. In particular, assessment of mitochondrial ROS generation provides an accurate picture of PCD-mediated lymphocyte depletion. In conclusion, alterations of mitochondrial function constitute an important feature of early PCD.
N Zamzami; P Marchetti; M Castedo; D Decaudin; A Macho; T Hirsch; S A Susin; P X Petit; B Mignotte; G Kroemer
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of experimental medicine     Volume:  182     ISSN:  0022-1007     ISO Abbreviation:  J. Exp. Med.     Publication Date:  1995 Aug 
Date Detail:
Created Date:  1995-09-07     Completed Date:  1995-09-07     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  2985109R     Medline TA:  J Exp Med     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  367-77     Citation Subset:  IM    
Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, Villejuif, France.
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MeSH Terms
Antioxidants / pharmacology
Cell Line
Cell Membrane / ultrastructure
Dexamethasone / pharmacology
Intracellular Membranes / ultrastructure
Lymphocytes / cytology*,  physiology
Membrane Potentials
Mice, Inbred BALB C
Mitochondria / physiology*
Reactive Oxygen Species / metabolism*
Spleen / cytology
Time Factors
Reg. No./Substance:
0/Antioxidants; 0/Reactive Oxygen Species; 50-02-2/Dexamethasone

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): J Exp Med
ISSN: 0022-1007
ISSN: 1540-9538
Publisher: The Rockefeller University Press
Article Information
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Print publication date: Day: 1 Month: 8 Year: 1995
Volume: 182 Issue: 2
First Page: 367 Last Page: 377
ID: 2192111
Publisher Id: 95355836
PubMed Id: 7629499

Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death

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