CDK4 Phosphorylates AMPKα2 to Inhibit Its Activity and Repress Fatty Acid Oxidation

Isabel C. Lopez-Mejia, Sylviane Lagarrigue, Albert Giralt, Laia Martinez-Carreres, Nadège Zanou, Pierre-Damien Denechaud, Judit Castillo-Armengol, Carine Chavey, Meritxell Orpinell, Brigitte Delacuisine, Anita Nasrallah, Caterina Collodet, Lianjun Zhang, Benoît Viollet, D. Grahame Hardie, Lluis Fajas (Lead / Corresponding author)

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24 Citations (Scopus)
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Abstract

The roles of CDK4 in the cell cycle have been extensively studied, but less is known about the mechanisms underlying the metabolic regulation by CDK4. Here, we report that CDK4 promotes anaerobic glycolysis and represses fatty acid oxidation in mouse embryonic fibroblasts (MEFs) by targeting the AMP-activated protein kinase (AMPK). We also show that fatty acid oxidation (FAO) is specifically induced by AMPK complexes containing the α2 subunit. Moreover, we report that CDK4 represses FAO through direct phosphorylation and inhibition of AMPKα2. The expression of non-phosphorylatable AMPKα2 mutants, or the use of a CDK4 inhibitor, increased FAO rates in MEFs and myotubes. In addition, Cdk4(-/-) mice have increased oxidative metabolism and exercise capacity. Inhibition of CDK4 mimicked these alterations in normal mice, but not when skeletal muscle was AMPK deficient. This novel mechanism explains how CDK4 promotes anabolism by blocking catabolic processes (FAO) that are activated by AMPK.

Original languageEnglish
Pages (from-to)336-349.e6
Number of pages20
JournalMolecular Cell
Volume68
Issue number2
Early online date19 Oct 2017
DOIs
Publication statusPublished - 19 Oct 2017

Keywords

  • CDK4
  • AMPK
  • FAO
  • Metabolism
  • Mitochondria

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