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

Isabel C Lopez-Mejia1, Sylviane Lagarrigue2, Albert Giralt3

  • 1Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.

Molecular Cell
|October 21, 2017
PubMed

Insights

Cyclin-dependent kinase 4 (CDK4) inhibits fatty acid oxidation (FAO) by blocking AMP-activated protein kinase (AMPK) signaling. This finding reveals a new metabolic regulatory mechanism for CDK4, impacting cellular energy balance.

Area of Science:

  • Cell Biology
  • Metabolism
  • Biochemistry

Background:

  • Cyclin-dependent kinase 4 (CDK4) is well-known for its role in cell cycle regulation.
  • Mechanisms by which CDK4 influences cellular metabolism are less understood.
  • CDK4's impact on metabolic pathways, particularly energy substrate utilization, requires further elucidation.

Purpose of the Study:

  • To investigate the role of CDK4 in regulating cellular metabolism.
  • To identify the molecular targets of CDK4 in metabolic control.
  • To understand how CDK4 influences glycolysis and fatty acid oxidation.

Main Methods:

  • Utilized mouse embryonic fibroblasts (MEFs) and myotubes.
  • Investigated the interaction between CDK4 and AMP-activated protein kinase (AMPK).
  • Employed non-phosphorylatable AMPKα2 mutants and CDK4 inhibitors.
  • Analyzed metabolic parameters including anaerobic glycolysis and fatty acid oxidation (FAO).
  • Studied Cdk4 knockout (Cdk4-/-) mice and assessed exercise capacity.

Main Results:

  • CDK4 was found to promote anaerobic glycolysis and repress fatty acid oxidation (FAO).
  • CDK4 directly phosphorylates and inhibits AMPKα2, a key regulator of FAO.
  • Genetic or pharmacological inhibition of CDK4 increased FAO rates.
  • Cdk4-/- mice exhibited enhanced oxidative metabolism and exercise capacity.
  • The effects of CDK4 inhibition on metabolism were dependent on AMPK signaling in skeletal muscle.

Conclusions:

  • CDK4 plays a significant role in metabolic regulation by inhibiting catabolic processes.
  • CDK4 represses fatty acid oxidation (FAO) via direct inhibition of AMPKα2.
  • This mechanism highlights how CDK4 promotes anabolism by suppressing FAO, impacting cellular energy homeostasis and potentially organismal traits like exercise capacity.
Keywords:
AMPKCDK4FAOmetabolismmitochondria

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