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FOXK1 and FOXK2 regulate aerobic glycolysis.

Journal article
Authors Valentina Sukonina
Haixia Ma
Wei Zhang
Stefano Bartesaghi
Santhilal Subhash
Mikael Heglind
Håvard Foyn
Mattias J. Betz
Daniel Nilsson
M. 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
Sven Enerbäck
Published in Nature
Volume 566
Pages 279-283
ISSN 1476-4687
Publication year 2019
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 279-283
Language en
Links dx.doi.org/10.1038/s41586-019-0900-...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Chemistry, Cell and Molecular Biology, Biochemistry, Cell Biology, Biochemistry and Molecular Biology

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.

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