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Context-dependent modification of PFKFB3 in hematopoietic stem cells promotes anaerobic glycolysis and ensures stress hematopoiesis.
Watanuki, Shintaro; Kobayashi, Hiroshi; Sugiura, Yuki; Yamamoto, Masamichi; Karigane, Daiki; Shiroshita, Kohei; Sorimachi, Yuriko; Fujita, Shinya; Morikawa, Takayuki; Koide, Shuhei; Oshima, Motohiko; Nishiyama, Akira; Murakami, Koichi; Haraguchi, Miho; Tamaki, Shinpei; Yamamoto, Takehiro; Yabushita, Tomohiro; Tanaka, Yosuke; Nagamatsu, Go; Honda, Hiroaki; Okamoto, Shinichiro; Goda, Nobuhito; Tamura, Tomohiko; Nakamura-Ishizu, Ayako; Suematsu, Makoto; Iwama, Atsushi; Suda, Toshio; Takubo, Keiyo.
Afiliação
  • Watanuki S; Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
  • Kobayashi H; Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
  • Sugiura Y; Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
  • Yamamoto M; Department of Cell Fate Biology and Stem Cell Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
  • Karigane D; Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan.
  • Shiroshita K; Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Sorimachi Y; Department of Research Promotion and Management, National Cerebral and Cardiovascular Center, Osaka, Japan.
  • Fujita S; Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
  • Morikawa T; Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
  • Koide S; Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
  • Oshima M; Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
  • Nishiyama A; Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
  • Murakami K; Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo, Japan.
  • Haraguchi M; Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
  • Tamaki S; Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
  • Yamamoto T; Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
  • Yabushita T; Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, University of Tokyo, Tokyo, Japan.
  • Tanaka Y; Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, University of Tokyo, Tokyo, Japan.
  • Nagamatsu G; Department of Immunology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.
  • Honda H; Department of Immunology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.
  • Okamoto S; Advanced Medical Research Center, Yokohama City University, Kanagawa, Japan.
  • Goda N; Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
  • Tamura T; Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
  • Nakamura-Ishizu A; Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan.
  • Suematsu M; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • Iwama A; International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
  • Suda T; Center for Advanced Assisted Reproductive Technologies, University of Yamanashi, Yamanashi, Japan.
  • Takubo K; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan.
Elife ; 122024 Apr 04.
Article em En | MEDLINE | ID: mdl-38573813
ABSTRACT
Metabolic pathways are plastic and rapidly change in response to stress or perturbation. Current metabolic profiling techniques require lysis of many cells, complicating the tracking of metabolic changes over time after stress in rare cells such as hematopoietic stem cells (HSCs). Here, we aimed to identify the key metabolic enzymes that define differences in glycolytic metabolism between steady-state and stress conditions in murine HSCs and elucidate their regulatory mechanisms. Through quantitative 13C metabolic flux analysis of glucose metabolism using high-sensitivity glucose tracing and mathematical modeling, we found that HSCs activate the glycolytic rate-limiting enzyme phosphofructokinase (PFK) during proliferation and oxidative phosphorylation (OXPHOS) inhibition. Real-time measurement of ATP levels in single HSCs demonstrated that proliferative stress or OXPHOS inhibition led to accelerated glycolysis via increased activity of PFKFB3, the enzyme regulating an allosteric PFK activator, within seconds to meet ATP requirements. Furthermore, varying stresses differentially activated PFKFB3 via PRMT1-dependent methylation during proliferative stress and via AMPK-dependent phosphorylation during OXPHOS inhibition. Overexpression of Pfkfb3 induced HSC proliferation and promoted differentiated cell production, whereas inhibition or loss of Pfkfb3 suppressed them. This study reveals the flexible and multilayered regulation of HSC glycolytic metabolism to sustain hematopoiesis under stress and provides techniques to better understand the physiological metabolism of rare hematopoietic cells.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosfofrutoquinase-2 / Glicólise Limite: Animals Idioma: En Revista: Elife Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Japão

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosfofrutoquinase-2 / Glicólise Limite: Animals Idioma: En Revista: Elife Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Japão