Differing roles of pyruvate dehydrogenase kinases during mouse oocyte maturation

Pyruvate dehydrogenase kinases (PDKs) modulate energy homeostasis in multiple tissues/cell types, under various nutrient conditions, through phosphorylation of the α subunit (PDHE1α) of the pyruvate dehydrogenase (PDH) complex. However, the roles of PDKs in meiotic maturation are currently unknown. Here, by employing morpholino knockdown and overexpression analysis of PDK paralogs (PDK1-4) in mouse oocytes, we established the site-specificity of PDKs toward the phosphorylation of three serine residues (Ser232, Ser293 and Ser300) on PDHE1α. We found that PDK3-mediated phosphorylation of Ser293-PDHE1α results in disruption of meiotic spindle morphology and chromosome alignment and decreased total ATP levels, probably through inhibition of PDH activity. Unexpectedly, we discovered that PDK1/2 promote meiotic maturation as their knockdown disturbs the assembly of meiotic apparatus, without significantly altered ATP content. Moreover, phosphorylation of Ser232-PDHE1α was demonstrated to mediate PDK1/2 action in meiotic maturation, possibly through a mechanism that is distinct from PDH inactivation. These findings reveal divergent roles of PDKs during oocyte maturation and indicate a novel mechanism controlling meiotic structure.