Document Detail


Hexokinase regulates Bax-mediated mitochondrial membrane injury following ischemic stress.
MedLine Citation:
PMID:  21430642     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Hexokinase (HK), the rate-limiting enzyme in glycolysis, controls cell survival by promoting metabolism and/or inhibiting apoptosis. Since HK isoforms I and II have mitochondrial targeting sequences, we attempted to separate the protective effects of HK on cell metabolism from those on apoptosis. We exposed renal epithelial cells to metabolic stress causing ATP depletion in the absence of glucose and found that this activated glycogen synthase kinase 3β (GSK3β) and Bax caused mitochondrial membrane injury and apoptosis. ATP depletion led to a progressive HK II dissociation from mitochondria, released mitochondrial apoptosis inducing factor and cytochrome c into the cytosol, activated caspase-3, and reduced cell survival. Compared with control, adenoviral-mediated HK I or II overexpression improved cell survival following stress, but did not prevent GSK3β or Bax activation, improve ATP content, or reduce mitochondrial fragmentation. HK I or HK II overexpression increased mitochondria-associated isoform-specific HK content, and decreased mitochondrial membrane injury and apoptosis after stress. In vivo, HK II localized exclusively to the proximal tubule. Ischemia reduced total renal HK II content and dissociated HK II from proximal tubule mitochondria. In cells overexpressing HK II, Bax and HK II did not interact before or after stress. While the mechanism by which HK antagonizes Bax-mediated apoptosis is unresolved by these studies, one possible scenario is that the two proteins compete for a common binding site on the outer mitochondrial membrane.
Authors:
Jonathan M Gall; Vincent Wong; David R Pimental; Andrea Havasi; Zhiyong Wang; John G Pastorino; Ramon G B Bonegio; John H Schwartz; Steven C Borkan
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-03-23
Journal Detail:
Title:  Kidney international     Volume:  79     ISSN:  1523-1755     ISO Abbreviation:  Kidney Int.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-05-13     Completed Date:  2011-09-13     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  0323470     Medline TA:  Kidney Int     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1207-16     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Animals
Apoptosis
Caspase 3 / metabolism
Cell Survival
Cells, Cultured
Cytochromes c / metabolism
Disease Models, Animal
Epithelial Cells / enzymology*,  pathology
Glucose / deficiency
Glycogen Synthase Kinase 3 / metabolism
Hexokinase / genetics,  metabolism*
Kidney Diseases / enzymology*,  pathology
Kidney Tubules, Proximal / blood supply,  enzymology*,  pathology
Mice
Mitochondrial Membranes / enzymology*,  pathology
Opossums
Protein Transport
Reperfusion Injury / enzymology*,  pathology
Signal Transduction
Stress, Physiological*
Time Factors
Transfection
bcl-2-Associated X Protein / metabolism*
Grant Support
ID/Acronym/Agency:
DK-53387/DK/NIDDK NIH HHS; F-30 DK 821503/DK/NIDDK NIH HHS; F30 DK082150/DK/NIDDK NIH HHS; K08 DK090143/DK/NIDDK NIH HHS; R0-1 DK-52898/DK/NIDDK NIH HHS; R01 DK052898/DK/NIDDK NIH HHS; R01 DK053387/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Bax protein, mouse; 0/bcl-2-Associated X Protein; 8L70Q75FXE/Adenosine Triphosphate; 9007-43-6/Cytochromes c; EC 2.7.1.1/HK1 protein, mouse; EC 2.7.1.1/Hexokinase; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3; EC 3.4.22.-/Caspase 3; IY9XDZ35W2/Glucose
Comments/Corrections
Comment In:
Kidney Int. 2011 Jun;79(11):1163-5   [PMID:  21566638 ]

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


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