FOXK1 and FOXK2 regulate aerobic glycolysis

Valentina Sukonina, Haixia Ma, Wei Zhang, Stefano Bartesaghi, Santhilal Subhash, Mikael Heglind, Håvard Foyn, Matthias J. Betz, Daniel Nilsson, Martin E. Lidell, Jennifer Naumann, Saskia Haufs-Brusberg, Henrik Palmgren, Tanmoy Mondal, Muheeb Beg, Mark P. Jedrychowski, Kjetil Taskén, Alexander Pfeifer, Xiao-Rong Peng, Chandrasekhar Kanduri and Sven Enerbäck ()
Additional contact information
Valentina Sukonina: University of Gothenburg
Haixia Ma: University of Gothenburg
Wei Zhang: University of Gothenburg
Stefano Bartesaghi: IMED Biotech Unit, AstraZenca
Santhilal Subhash: University of Gothenburg
Mikael Heglind: University of Gothenburg
Håvard Foyn: Oslo University Hospital
Matthias J. Betz: University of Gothenburg
Daniel Nilsson: University of Gothenburg
Martin E. Lidell: University of Gothenburg
Jennifer Naumann: University Hospital Bonn
Saskia Haufs-Brusberg: University Hospital Bonn
Henrik Palmgren: IMED Biotech Unit, AstraZenca
Tanmoy Mondal: University of Gothenburg
Muheeb Beg: University of Gothenburg
Mark P. Jedrychowski: Harvard University Medical School
Kjetil Taskén: Oslo University Hospital
Alexander Pfeifer: University Hospital Bonn
Xiao-Rong Peng: IMED Biotech Unit, AstraZenca
Chandrasekhar Kanduri: University of Gothenburg
Sven Enerbäck: University of Gothenburg

Nature, 2019, vol. 566, issue 7743, 279-283

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-0900-5

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