2. Academic Validation
  3. Rhythmic glucose metabolism regulates the redox circadian clockwork in human red blood cells

Rhythmic glucose metabolism regulates the redox circadian clockwork in human red blood cells

  • Nat Commun. 2021 Jan 15;12(1):377. doi: 10.1038/s41467-020-20479-4.
Ratnasekhar Ch # 1 2,  Guillaume Rey # 1 3,  Sandipan Ray 4 5 6,  Pawan K Jha 4 5,  Paul C Driscoll 7,  Mariana Silva Dos Santos 7,  Dania M Malik 4 5,  Radoslaw Lach 1 8,  Aalim M Weljie 4 5,  James I MacRae 7,  Utham K Valekunja 4 5,  Akhilesh B Reddy 9 10 11 12
Affiliations

Affiliations

  • 1 University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
  • 2 School of Biological Sciences, Queen's University Belfast, Belfast, BT9 5DL, UK.
  • 3 Unilabs Genetics Laboratory, 1003, Lausanne, Switzerland.
  • 4 Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, 19104, USA.
  • 5 Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 6 Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, 502285, Telangana, India.
  • 7 The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
  • 8 Department of Oncology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.
  • 9 Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, 19104, USA. areddy@cantab.net.
  • 10 Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. areddy@cantab.net.
  • 11 Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. areddy@cantab.net.
  • 12 Chronobiology and Sleep institute (CSI), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. areddy@cantab.net.
  • # Contributed equally.
PMID: 33452240 DOI: 10.1038/s41467-020-20479-4
Abstract

Circadian clocks coordinate mammalian behavior and physiology enabling organisms to anticipate 24-hour cycles. Transcription-translation feedback loops are thought to drive these clocks in most of mammalian cells. However, red blood cells (RBCs), which do not contain a nucleus, and cannot perform transcription or translation, nonetheless exhibit circadian redox rhythms. Here we show human RBCs display circadian regulation of glucose metabolism, which is required to sustain daily redox oscillations. We found daily rhythms of metabolite levels and flux through glycolysis and the pentose phosphate pathway (PPP). We show that inhibition of critical Enzymes in either pathway abolished 24-hour rhythms in metabolic flux and redox oscillations, and determined that metabolic oscillations are necessary for redox rhythmicity. Furthermore, metabolic flux rhythms also occur in nucleated cells, and persist when the core transcriptional circadian clockwork is absent in Bmal1 knockouts. Thus, we propose that rhythmic glucose metabolism is an integral process in circadian rhythms.

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