HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity
| Autor: | Ichiro Manabe, Yuki Sugiura, Ryozo Nagai, Yoshifumi Yamaguchi, Takayuki Isagawa, Kurara Honda, Masaki Wake, Keimon Sayama, Katsura Soma, Randall S. Johnson, Hajime Abe, Hiroaki Semba, Norihiko Takeda, Manami Katoh, Katsuhiro Koyama, Andrew S. Cowburn, Dana M. R. Jenkins, Jung Whan Kim, Issei Komuro, Nobuhito Goda, Hyunsung Choi, Masayuki Miura, Masataka Asagiri, Hidenobu Miyazawa |
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| Přispěvatelé: | Yamaguchi, Yoshifumi [0000-0001-7340-4557], Johnson, Randall S [0000-0002-4084-6639], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
PYRUVATE-DEHYDROGENASE KINASE General Physics and Astronomy ACTIVATION Cell Movement Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase Glycolysis Hypoxia Oxidase test Multidisciplinary ATP synthase Protein-Serine-Threonine Kinases Cell biology Multidisciplinary Sciences Biochemistry Hypoxia-inducible factors Science & Technology - Other Topics medicine.symptom EXPRESSION Pyruvate dehydrogenase kinase Science HYPOXIA-INDUCIBLE FACTOR FACTOR-I Primary Cell Culture Inflammation Biology PKM2 Carbohydrate metabolism Protein Serine-Threonine Kinases General Biochemistry Genetics and Molecular Biology Article MECHANISMS Electron Transport Complex IV 03 medical and health sciences INFLAMMATION Cell Line Tumor medicine Animals Science & Technology Dichloroacetic Acid Macrophages Pyruvate Dehydrogenase Acetyl-Transferring Kinase General Chemistry Hypoxia-Inducible Factor 1 alpha Subunit OXYGEN-CONSUMPTION Mice Inbred C57BL MICE 030104 developmental biology Glucose CELLS biology.protein |
| Zdroj: | Nature Communications Nature Communications, Vol 7, Iss 1, Pp 1-10 (2016) |
| ISSN: | 2041-1723 |
| Popis: | In severely hypoxic condition, HIF-1α-mediated induction of Pdk1 was found to regulate glucose oxidation by preventing the entry of pyruvate into the tricarboxylic cycle. Monocyte-derived macrophages, however, encounter a gradual decrease in oxygen availability during its migration process in inflammatory areas. Here we show that HIF-1α-PDK1-mediated metabolic changes occur in mild hypoxia, where mitochondrial cytochrome c oxidase activity is unimpaired, suggesting a mode of glycolytic reprogramming. In primary macrophages, PKM2, a glycolytic enzyme responsible for glycolytic ATP synthesis localizes in filopodia and lammelipodia, where ATP is rapidly consumed during actin remodelling processes. Remarkably, inhibition of glycolytic reprogramming with dichloroacetate significantly impairs macrophage migration in vitro and in vivo. Furthermore, inhibition of the macrophage HIF-1α-PDK1 axis suppresses systemic inflammation, suggesting a potential therapeutic approach for regulating inflammatory processes. Our findings thus demonstrate that adaptive responses in glucose metabolism contribute to macrophage migratory activity. Migration to the inflamed tissue demands energy production in an increasingly hypoxic environment. Here the authors show that during migration, HIF1α-induced PDK1 uniquely adapts macrophage metabolism to mild hypoxia by promoting glycolysis while preserving cytochrome c oxidase activity. |
| Databáze: | OpenAIRE |
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