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

Lia Heinemann-Yerushalmi, Lital Bentovim, Neta Felsenthal, Nofar Michaeli, Sharon Krief, Rebecca Haffner-Krausz, Shifra Ben-Dor, Maxim Itkin, Sergey Malitsky, Alon Silberman, Ayelet Erez, Elazar Zelzer
2020 bioRxiv   pre-print
AbstractPyruvate dehydrogenase kinase family of enzymes (PDK1-4) are central negative regulators of the TCA cycle by phosphorylating the rate-limiting multi-enzyme pyruvate dehydrogenase complex (PDC). Here, we show that the PDK family is dispensable for murine embryonic development and that BCKDK serves as a compensatory mechanism for PDKs by inactivating PDC.To study the role of Pdk family in vivo, we knocked out all four genes one by one. Surprisingly, Pdk total KO mouse embryos developed
more » ... mbryos developed and were born in the expected ratio. Postnatally, these mice died by day four due to hypoglycemia or ketoacidosis, as confirmed by deep metabolic profiling.Looking for the mechanism that enables development in the absence of Pdk'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 (Bckdk), a key regulator in the catabolism of branched chain amino acids (BCAA), as a candidate. Knockout of both Bckdk and the entire Pdk 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.
doi:10.1101/2020.03.22.002360 fatcat:ouvigr3wevdjxi3nbz7jnea2fu