Document Detail


Glucose-6-phosphate isomerase deficiency results in mTOR activation, failed translocation of lipin 1α to the nucleus and hypersensitivity to glucose: Implications for the inherited glycolytic disease.
MedLine Citation:
PMID:  21787864     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Inherited glucose-6-phosphate isomerase (GPI) deficiency is the second most frequent glycolytic erythroenzymopathy in humans. Patients present with non-spherocytic anemia of variable severity and with neuromuscular dysfunction. We previously described Chinese hamster (CHO) cell lines with mutations in GPI and loss of GPI activity. This resulted in a temperature sensitivity and severe reduction in the synthesis of glycerolipids due to a reduction in phosphatidate phosphatase (PAP). In the current article we attempt to describe the nature of this pleiotropic effect. We cloned and sequenced the CHO lipin 1 cDNA, a gene that codes for PAP activity. Overexpression of lipin 1 in the GPI-deficient cell line, GroD1 resulted in increased PAP activity, however it failed to restore glycerolipid biosynthesis. Fluorescence microscopy showed a failure of GPI-deficient cells to localize lipin 1α to the nucleus. We also found that glucose-6-phosphate levels in GroD1 cells were 10-fold over normal. Lowering glucose levels in the growth medium partially restored glycerolipid biosynthesis and nuclear localization of lipin 1α. Western blot analysis of the elements within the mTOR pathway, which influences lipin 1 activity, was consistent with an abnormal activation of this system. Combined, these data suggest that GPI deficiency results in an accumulation of glucose-6-phosphate, and possibly other glucose-derived metabolites, leading to activation of mTOR and sequestration of lipin 1 to the cytosol, preventing its proper functioning. These results shed light on the mechanism underlying the pathologies associated with inherited GPI deficiency and the variability in the severity of the symptoms observed in these patients.
Authors:
Jorge F Haller; Sarah A Krawczyk; Lubov Gostilovitch; Barbara E Corkey; Raphael A Zoeller
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-07-21
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1812     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-10-03     Completed Date:  2011-11-29     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1393-402     Citation Subset:  IM    
Copyright Information:
2011 Elsevier B.V. All rights reserved.
Affiliation:
Department of Physiology and Biophysics, Boston University School of Medicine, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Anemia, Hemolytic, Congenital Nonspherocytic / etiology*
Animals
Blotting, Western
CHO Cells
Cell Nucleus / metabolism*
Cloning, Molecular
Cricetinae
Electrophoretic Mobility Shift Assay
Fructosephosphates / metabolism
Glucose / pharmacology*
Glucose-6-Phosphate / metabolism
Glucose-6-Phosphate Isomerase / genetics,  metabolism*
Glycolipids
Microscopy, Fluorescence
Molecular Sequence Data
Organic Chemicals / metabolism
Phosphatidate Phosphatase / metabolism
Protein Transport
Sequence Homology, Amino Acid
TOR Serine-Threonine Kinases / metabolism*
Grant Support
ID/Acronym/Agency:
P30 DK046200-10S1/DK/NIDDK NIH HHS; R01 DK035914/DK/NIDDK NIH HHS; R01 DK056690-12/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Fructosephosphates; 0/Glycolipids; 0/Organic Chemicals; 0/glycerolglycolipids; 0/lipine; 50-99-7/Glucose; 56-73-5/Glucose-6-Phosphate; 6814-87-5/fructose-6-phosphate; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 3.1.3.4/Phosphatidate Phosphatase; EC 5.3.1.9/Glucose-6-Phosphate Isomerase
Comments/Corrections

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