BCKDK regulates the TCA cycle through PDC in the absence of PDK family during embryonic development.
Dev Cell
; 56(8): 1182-1194.e6, 2021 04 19.
Article
in En
| MEDLINE
| ID: mdl-33773101
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein Kinases
/
Pyruvate Dehydrogenase Complex
/
Citric Acid Cycle
/
Embryonic Development
/
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Dev Cell
Journal subject:
EMBRIOLOGIA
Year:
2021
Document type:
Article
Affiliation country:
Israel