Pyruvate dehydrogenase dependent metabolic program affects oligodendrocyte maturation and remyelination

Abstract

AbstractThe metabolic need of the premature oligodendrocytes (Pre-OLs) and mature oligodendrocytes (OLs) are distinct. The metabolic control of oligodendrocyte maturation is not fully understood. Here we show that the terminal maturation and higher mitochondrial respiration in the oligodendrocyte is an integrated process controlled through pyruvate dehydrogenase (Pdh). Combined bioenergetics and metabolic studies show that mature oligodendrocytes show elevated TCA cycle activity than the premature oligodendrocytes. Our signaling studies show that the increased TCA cycle activity is mediated by the activation of Pdh due to inhibition of pyruvate dehydrogenases isoform-1 (Pdhk1) that phosphorylates and inhibits Pdh. Accordingly, when Pdhk1 is directly expressed in the premature oligodendrocytes, they fail to mature. While Pdh converts pyruvate into the acetyl-CoA by its oxidative decarboxylation, our study shows that Pdh also activates a unique molecular switch required for oligodendrocyte maturation by acetylating the bHLH family transcription factor Olig1. Pdh inhibition via Pdhk1 blocks the Olig1-acetylation and hence, oligodendrocyte maturation. Using the cuprizone model of demyelination, we show that Pdh is deactivated during the demyelination phase, which is reversed in the remyelination phase upon cuprizone withdrawal. In addition, Pdh activity status correlates with the Olig1-acetylation status. Hence, the Pdh metabolic node activation allows a robust mitochondrial respiration and activation of a molecular program necessary for the terminal maturation of oligodendrocytes. Our findings open a new dialogue in the developmental biology that links cellular development and metabolism. These findings have far-reaching implications for the development of therapies for a variety of demyelinating disorders including multiple sclerosis.