BCKDK regulates the TCA cycle through PDC in the absence of PDK family during embryonic development

Summary Pyruvate dehydrogenase kinases (PDK1–4) inhibit the TCA cycle by phosphorylating pyruvate complex (PDC). Here, we show that PDK family is dispensable for murine embryonic development and BCKDK serves as a compensatory mechanism inactivating PDC. First, knocked out all four Pdk genes one one. Surprisingly, total KO embryos developed were born in expected ratios but died postnatal day 4 because of hypoglycemia or ketoacidosis. Moreover, PDC was phosphorylated these embryos, suggesting another kinase compensates family. Bioinformatic analysis implicated branched-chain ketoacid (Bckdk), key regulator amino acids (BCAAs) catabolism. Indeed, knockout Bckdk led to loss phosphorylation, an increase activity entry into cycle, lethality. These findings reveal regulatory crosstalk hardwiring BCAA glucose catabolic pathways, which feed cycle.