University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
School of Biological Sciences, Queen's University Belfast, Belfast, BT9 5DL, UK.
Nat Commun. 2021 Jan 15;12(1):377. doi: 10.1038/s41467-020-20479-4.
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.
生物钟协调哺乳动物的行为和生理机能,使生物能够预测 24 小时的周期。转录-翻译反馈回路被认为是大多数哺乳动物细胞中驱动这些生物钟的机制。然而,红细胞(RBC)不含细胞核,不能进行转录或翻译,但仍表现出昼夜节律的氧化还原节律。在这里,我们展示了人类 RBC 表现出葡萄糖代谢的昼夜调节,这是维持每日氧化还原振荡所必需的。我们发现了糖酵解和磷酸戊糖途径(PPP)中代谢物水平和通量的每日节律。我们表明,抑制两条途径中的关键酶会消除代谢通量和氧化还原振荡的 24 小时节律,并确定代谢振荡是氧化还原节律性所必需的。此外,代谢通量节律也发生在有核细胞中,并且在 Bmal1 基因敲除小鼠中核心转录生物钟缺失时仍然存在。因此,我们提出,节律性葡萄糖代谢是昼夜节律的一个组成过程。