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

Ratnasekhar Ch, Guillaume Rey, Sandipan Ray, Pawan K. Jha, Paul C. Driscoll, Mariana Silva Santos, Dania M. Malik, Radoslaw Lach, Aalim M. Weljie, James I. MacRae, Utham K. Valekunja and Akhilesh B. Reddy ()
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Ratnasekhar Ch: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke’s Hospital
Guillaume Rey: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke’s Hospital
Sandipan Ray: University of Pennsylvania
Pawan K. Jha: University of Pennsylvania
Paul C. Driscoll: The Francis Crick Institute
Mariana Silva Santos: The Francis Crick Institute
Dania M. Malik: University of Pennsylvania
Radoslaw Lach: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke’s Hospital
Aalim M. Weljie: University of Pennsylvania
James I. MacRae: The Francis Crick Institute
Utham K. Valekunja: University of Pennsylvania
Akhilesh B. Reddy: University of Pennsylvania

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20479-4

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