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

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.

Response to Comment on “Circadian rhythms in the absence of the clock gene Bmal1 ”

“…Several independent lines of evidence demonstrate molecular and metabolic oscillations in the absence of Bmal1 (7,8) or an alternative clock knockout model [Cryptochrome-deficient mice (9)], supporting our observations. To establish that transcriptome-level oscillations observed in Bmal1 -/cells are "noise" rather than true circadian rhythmicity, the authors could perform identical experiments within an environment that they think is completely devoid of external cues to verify that there are absolutely no 24-hour molecular oscillations in cultured Bmal1 -/cells under constant conditions.…”

Response to Comment on “Circadian rhythms in the absence of the clock gene Bmal1 ”

“…2, F and G). Furthermore, Bmal1 -/skin fibroblasts show circadian metabolic flux oscillations under constant conditions (15). These data provide further evidence of self-sustained circadian oscillations in Bmal1 -/cells and tissues under constant conditions.…”

Luteolin promotes macrophage-mediated phagocytosis by inhibiting CD47 pyroglutamation

“…nucleus, mitochondria, endoplasmic reticulum etc.) [ 8 , 9 ] and catalyzes the formation of N-terminal pyroglutamate (pGlu) by converting glutamate/glutamine to pGlu residue similar as the secretory isoenzyme Glutaminyl cyclases (QC) [ 1 , 10 , 11 ]. Prior researches have indicated that isoQC is the critical regulator of pGlu modification of CD47 N-terminal peptide and resultantly affects the interaction between CD47 and SIRPα [ 12 , 13 ].…”