Journal Article

FOXK1 and FOXK2 regulate aerobic glycolysis

Haufs-Brusberg, Saskia, Beg, Muheeb, Enerbäck, Sven, Subhash, Santhilal, Taskén, Kjetil, Pfeifer, Alexander, Sukonina, Valentina, Naumann, Jennifer, Zhang, Wei, Foyn, Håvard, Ma, Haixia, Jedrychowski, Mark P., Nilsson, Daniel, Mondal, Tanmoy, Kanduri, Chandrasekhar, Betz, Matthias J., Heglind, Mikael, Lidell, Martin E., Palmgren, Henrik, Bartesaghi, Stefano, Peng, Xiao-Rong

2019

Overview

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 flexibility 1 . 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 nutrients 2 . 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. The Forkhead transcription factors FOXK1 and FOXK2, which are induced by starvation, reprogram cellular metabolism to induce aerobic glycolysis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38 / 38/1 / 38/109 / 38/22 / 38/77 / 38/89 / 38/90 / 38/91 / 3T3 Cells / 631/443/319/1642/137/773 / 631/80/304 / Adaptation / Adipocytes / Aerobiosis / Andra medicinska och farmaceutiska grundvetenskaper / Animals / Bioenergetics / Bioinformatics / Catalysis / Cell and Molecular Biology / Cell Biology / Cell- och molekylärbiologi / Cellbiologi / Cells (Biology) / Cells, Cultured / Dehydrogenase / Dehydrogenases / DNA binding proteins / Enzymes / Experiments / Female / Forkhead protein / Forkhead Transcription Factors - deficiency / Forkhead Transcription Factors - genetics / Forkhead Transcription Factors - metabolism / Gene expression / Genomes / Glucose / Glucose metabolism / Glycolysis / Health aspects / Hexokinase / Humanities and Social Sciences / Humans / In vivo methods and tests / Kinases / L-Lactate dehydrogenase / Lactate dehydrogenase / Lactic acid / Lactic Acid - biosynthesis / Lactic Acid - metabolism / Letter / Machinery / Male / Metabolism / Mice / Mice, Inbred C57BL / Mitochondria / Mitochondria - enzymology / Mitochondria - metabolism / Molecular Biology / Molekylärbiologi / multidisciplinary / Muscle Fibers, Skeletal - metabolism / Musculoskeletal system / Nutrients / Other Basic Medicine / Oxidation / Oxidation-Reduction / Oxidation-reduction reactions / Phenotypes / Phosphatases / Phosphofructokinase / Phosphorylation / Protein-Serine-Threonine Kinases - metabolism / Pyruvate dehydrogenase (lipoamide) / Pyruvate Dehydrogenase (Lipoamide)-Phosphatase - metabolism / Pyruvate Dehydrogenase Complex - chemistry / Pyruvate Dehydrogenase Complex - metabolism / Pyruvate kinase / Pyruvic acid / Pyruvic Acid - metabolism / Regulators / Science / Science (multidisciplinary) / Starvation / Substrates / Thermogenesis / Transcription factors