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

Looking for the mechanism that enables development in the absence of ’s, we found that PDC site 2 (S300) was phosphorylated in these embryos, suggesting that another kinase compensates for the PDK family. Bioinformatic analysis predicted brunch chain ketoacid dehydrogenase kinase (, a key regulator in the catabolism of branched chain amino acids (BCAA), as a candidate. Knockout of both and the entire family led to loss of PDC phosphorylation on S300 and early embryonic lethality which firmly establish the role of BCKDK in the regulation of PDC. Altogether, this work demonstrates a redundancy for the PDK family during development and identifies BCKDK regulation of PDC as a backup mechanism that allows embryonic development. More broadly, BCKDK regulation of PDC reveals a new regulatory crosstalk hardwiring BCAA and glucose catabolic pathways, which feed the TCA cycle.