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

Dev Cell. 2021 Apr 19;56(8):1182-1194.e6. doi: 10.1016/j.devcel.2021.03.007. Epub 2021 Mar 26.

Abstract

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

Keywords: BCAA; BCKDK; PDC; PDK; TCA cycle; embryogenesis; glycolysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Citric Acid Cycle*
  • Embryo Loss / enzymology
  • Embryo Loss / pathology
  • Embryonic Development*
  • Gene Deletion
  • Hypoglycemia / complications
  • Hypoglycemia / enzymology
  • Hypoglycemia / pathology
  • Ketosis / complications
  • Ketosis / enzymology
  • Ketosis / pathology
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / metabolism*
  • Pyruvate Dehydrogenase Complex / metabolism*
  • Pyruvic Acid / metabolism

Substances

  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Pyruvate Dehydrogenase Complex
  • Pyruvic Acid
  • Protein Kinases
  • (3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase