FOXK1 and FOXK2 regulate aerobic glycolysis

Nature. 2019 Feb;566(7743):279-283. doi: 10.1038/s41586-019-0900-5. Epub 2019 Jan 30.

Abstract

Adaptation to the environment and extraction of energy are essential for survival. Some species have found niches and specialized in using a particular source of energy, whereas others-including humans and several other mammals-have developed a high degree of flexibility1. A lot is known about the general metabolic fates of different substrates but we still lack a detailed mechanistic understanding of how cells adapt in their use of basic nutrients2. Here we show that the closely related fasting/starvation-induced forkhead transcription factors FOXK1 and FOXK2 induce aerobic glycolysis by upregulating the enzymatic machinery required for this (for example, hexokinase-2, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase), while at the same time suppressing further oxidation of pyruvate in the mitochondria by increasing the activity of pyruvate dehydrogenase kinases 1 and 4. Together with suppression of the catalytic subunit of pyruvate dehydrogenase phosphatase 1 this leads to increased phosphorylation of the E1α regulatory subunit of the pyruvate dehydrogenase complex, which in turn inhibits further oxidation of pyruvate in the mitochondria-instead, pyruvate is reduced to lactate. Suppression of FOXK1 and FOXK2 induce the opposite phenotype. Both in vitro and in vivo experiments, including studies of primary human cells, show how FOXK1 and/or FOXK2 are likely to act as important regulators that reprogram cellular metabolism to induce aerobic glycolysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Aerobiosis*
  • Animals
  • Cells, Cultured
  • Female
  • Forkhead Transcription Factors / deficiency
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Glycolysis*
  • Humans
  • Lactic Acid / biosynthesis
  • Lactic Acid / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / enzymology
  • Mitochondria / metabolism
  • Muscle Fibers, Skeletal / metabolism
  • Oxidation-Reduction
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyruvate Dehydrogenase (Lipoamide)-Phosphatase / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Pyruvate Dehydrogenase Complex / chemistry
  • Pyruvate Dehydrogenase Complex / metabolism
  • Pyruvic Acid / metabolism

Substances

  • FOXK1 protein, human
  • Forkhead Transcription Factors
  • FoxK2 protein, mouse
  • Foxk1 protein, mouse
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Pyruvate Dehydrogenase Complex
  • interleukin binding factor
  • Lactic Acid
  • Pyruvic Acid
  • Protein-Serine-Threonine Kinases
  • Pyruvate Dehydrogenase (Lipoamide)-Phosphatase