Document Detail


Metabolic preconditioning of mammalian cells: mimetic agents for hypoxia lack fidelity in promoting phosphorylation of pyruvate dehydrogenase.
MedLine Citation:
PMID:  23138570     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Induction of HIF-1α by oxygen limitation promotes increased phosphorylation and catalytic depression of mitochondrial pyruvate dehydrogenase (PDH) and an enhanced glycolytic poise in cells. Cobalt chloride and desferrioxamine are widely used as mimics for hypoxia because they increase the levels of HIF-1α. We evaluated the ability of these agents to elicit selected physiological responses to hypoxia as a means to metabolically precondition mammalian cells, but without the detrimental effects of hypoxia. We show that, while CoCl(2) does increase HIF-1α in a dose-dependent manner, it unexpectedly and strikingly decreases PDH phosphorylation at E1α sites 1, 2, and 3 (Ser(293), Ser(300), and Ser(232), respectively) in HepG2 cells. This same effect is also observed for site 1 in mouse NIH/3T3 fibroblasts and J774 macrophages. CoCl(2) unexpectedly decreases the mRNA expression for PDH kinase-2 in HepG2 cells, which likely explains the dephosphorylation of PDH observed. And nor does desferrioxamine promote the expected increase in PDH phosphorylation. Dimethyloxaloylglycine (a prolyl hydroxylase inhibitor) performs better in this regard, but failed to promote the stronger effects seen with hypoxia. Consequently, CoCl(2) and desferrioxamine are unreliable mimics of hypoxia for physiological events downstream of HIF-1α stabilization. Our study demonstrates that mimetic chemicals must be chosen with caution and evaluated thoroughly if bona fide cellular outcomes are to be promoted with fidelity.
Authors:
Apurva Borcar; Michael A Menze; Mehmet Toner; Steven C Hand
Publication Detail:
Type:  Journal Article     Date:  2012-11-09
Journal Detail:
Title:  Cell and tissue research     Volume:  351     ISSN:  1432-0878     ISO Abbreviation:  Cell Tissue Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-04     Completed Date:  2013-06-05     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  0417625     Medline TA:  Cell Tissue Res     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  99-106     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Acids, Dicarboxylic / pharmacology
Animals
Blotting, Western
Cell Hypoxia / drug effects
Cell Line
Cobalt / pharmacology
Deferoxamine / pharmacology
Gene Expression Regulation, Enzymologic / drug effects
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Mammals / metabolism*
Mice
Phosphorylation / drug effects
Pyruvate Dehydrogenase Complex / genetics,  metabolism*
RNA, Messenger / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
R01 DK046270/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Amino Acids, Dicarboxylic; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Pyruvate Dehydrogenase Complex; 0/RNA, Messenger; 0/pyruvate dehydrogenase multienzyme complex E1; 3G0H8C9362/Cobalt; 5262-39-5/oxalylglycine; 7646-79-9/cobaltous chloride; J06Y7MXW4D/Deferoxamine
Comments/Corrections

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


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