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BCKDK regulates the TCA cycle through PDC in the absence of PDK family during embryonic development.
Heinemann-Yerushalmi, Lia; Bentovim, Lital; Felsenthal, Neta; Vinestock, Ron Carmel; Michaeli, Nofar; Krief, Sharon; Silberman, Alon; Cohen, Marina; Ben-Dor, Shifra; Brenner, Ori; Haffner-Krausz, Rebecca; Itkin, Maxim; Malitsky, Sergey; Erez, Ayelet; Zelzer, Elazar.
Afiliación
  • Heinemann-Yerushalmi L; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Bentovim L; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Felsenthal N; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Vinestock RC; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Michaeli N; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Krief S; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Silberman A; Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Cohen M; Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Ben-Dor S; Bioinformatics and Biological Computing Unit, Biological Services, Weizmann Institute of Science, Rehovot, 76100, Israel.
  • Brenner O; Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Haffner-Krausz R; Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Itkin M; Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Malitsky S; Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Erez A; Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Zelzer E; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address: eli.zelzer@weizmann.ac.il.
Dev Cell ; 56(8): 1182-1194.e6, 2021 04 19.
Article en En | MEDLINE | ID: mdl-33773101
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Quinasas / Complejo Piruvato Deshidrogenasa / Ciclo del Ácido Cítrico / Desarrollo Embrionario / Piruvato Deshidrogenasa Quinasa Acetil-Transferidora Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Dev Cell Asunto de la revista: EMBRIOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Quinasas / Complejo Piruvato Deshidrogenasa / Ciclo del Ácido Cítrico / Desarrollo Embrionario / Piruvato Deshidrogenasa Quinasa Acetil-Transferidora Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Dev Cell Asunto de la revista: EMBRIOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Estados Unidos