Abstract
Loss of Oligodendrocytes in Mouse Model of Pyruvate Dehydrogenase Complex Deficiency and Partial Reversal by Phenylbutyrate Treatment
Highlights
Pyruvate Dehydrogenase Complex (PDC), a mitochondrial matrix enzyme, converts pyruvate, the end product of cytoplasmic glycolysis, into acetyl-coenzyme A which is further metabolized in the citric acid cycle
In the present study we show that the population of OLGs is severely affected by pyruvate dehydrogenase (PDH)+/- mutation but may be partially restored by PB treatment which reconstitutes their proliferating OLG Progenitor Cells (OPCs)
In 35-day-old mice the PDH+/- mutation reduced the overall populations of OLG, their precursor OPCs as well as total cell proliferation in the analyzed brain regions
Summary
Pyruvate Dehydrogenase Complex (PDC), a mitochondrial matrix enzyme, converts pyruvate, the end product of cytoplasmic glycolysis, into acetyl-coenzyme A which is further metabolized in the citric acid cycle. PDC consists of a thiamine diphosphate-dependent pyruvate dehydrogenase (PDH), a heterotetramer of 2α and 2β subunits (α2β2); dihydrolipoamide acetyltransferase, and FAD-containing dihydrolipoamide dehydrogenase (E3), which is integrated into the complex by an E3-binding protein (E3BP) [1,2,3,4]. PDC is regulated through phosphorylation of the α-subunit of PDH by four pyruvate dehydrogenase kinase (PDK) isoforms at three specific serine residues (Site 1: Ser264; Site 2: Ser271; and Site 3: Ser203) [5]. Phosphorylation at any one of these sites renders the complex inactive. PDK isoforms exhibit different specificities for the three PDHα serine sites.
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