Phosphorylation status of pyruvate dehydrogenase distinguishes metabolic phenotypes of cultured rat brain astrocytes and neurons.
Glucose metabolism in nervous tissue has been proposed to occur in a compartmentalized manner with astrocytes contributing largely to glycolysis and neurons being the primary site of glucose oxidation. However, mammalian astrocytes and neurons both contain mitochondria, and it remains unclear why in culture neurons oxidize glucose, lactate, and pyruvate to a much larger extent than astrocytes. The objective of this study was to determine whether pyruvate metabolism is differentially regulated in cultured neurons versus astrocytes. Expression of all components of the pyruvate dehydrogenase complex (PDC), the rate-limiting step for pyruvate entry into the Krebs cycle, was determined in cultured astrocytes and neurons. In addition, regulation of PDC enzymatic activity in the two cell types via protein phosphorylation was examined. We show that all components of the PDC are expressed in both cell types in culture, but that PDC activity is kept strongly inhibited in astrocytes through phosphorylation of the pyruvate dehydrogenase alpha subunit (PDH alpha). In contrast, neuronal PDC operates close to maximal levels with much lower levels of phosphorylated PDH alpha. Dephosphorylation of astrocytic PDH alpha restores PDC activity and lowers lactate production. Our findings suggest that the glucose metabolism of astrocytes and neurons may be far more flexible than previously believed.
Halim
Nader D
ND
Graduate Program in Molecular and Cell Biology, Uniformed Services University, Bethesda, Maryland 20814, USA.
Mcfate
Thomas
T
Mohyeldin
Ahmed
A
Okagaki
Peter
P
Korotchkina
Lioubov G
LG
Patel
Mulchand S
MS
Jeoung
Nam Ho
NH
Harris
Robert A
RA
Schell
Michael J
MJ
Verma
Ajay
A
D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000378:metabolism*; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D015180:Electrophoresis, Gel, Two-Dimensional; D015151:Immunoblotting; D007150:Immunohistochemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D011768:Pyruvate Dehydrogenase Complex; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase