Phosphorylation status of pyruvate dehydrogenase distinguishes metabolic phenotypes of cultured rat brain astrocytes and neurons

TLDR

Glucose metabolism in nervous tissue is compartmentalized, with astrocytes mainly glycolytic and neurons primarily oxidizing glucose, yet both cell types possess mitochondria and neurons oxidize substrates more extensively than astrocytes. This study aimed to determine whether pyruvate metabolism is differentially regulated in cultured neurons versus astrocytes. The authors quantified expression of all pyruvate dehydrogenase complex components and examined PDC enzymatic activity regulation via phosphorylation in cultured astrocytes and neurons. All PDC components were expressed in both cell types, but astrocytes maintained strong PDC inhibition through PDHα phosphorylation, whereas neurons had near‑maximal activity with low phosphorylation; dephosphorylating astrocytic PDHα restored activity and reduced lactate, indicating greater metabolic flexibility than previously thought. © 2010 Wiley‑Liss, Inc.

Abstract

Abstract 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 (PDHα). In contrast, neuronal PDC operates close to maximal levels with much lower levels of phosphorlyated PDHα. Dephosphorylation of astrocytic PDHα 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. © 2010 Wiley‐Liss, Inc.