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Rhythmic glucose metabolism regulates the redox circadian clockwork in human red blood cells (LC-MS)

ABSTRACT:

Circadian clocks coordinate mammalian behaviour 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.

LC-MS assay protocols and data are reported in the current study MTBLS1285.

GC-MS assay protocols and data for this study are reported in MTBLS1286.

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic

SUBMITTER: Ratnasekhar Ch

PROVIDER: MTBLS1285 | MetaboLights | 2020-11-13

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS1285	Other
	FILES	Other
	a_MTBLS1285_LC-MS_alternating_hilic_metabolite_profiling-1.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS1285_LC-MS_alternating_hilic_metabolite_profiling-1_v2_maf.tsv	Tabular

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Rhythmic glucose metabolism regulates the redox circadian clockwork in human red blood cells (GC-MS)

Project description:Circadian clocks coordinate mammalian behaviour 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. GC-MS assay protocols and data are reported in the current study MTBLS1286.LC-MS assay protocols and data for this study are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1285' rel='noopener noreferrer' target='_blank'>MTBLS1285</a>.

2020-11-13 | MTBLS1286 | MetaboLights

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Project description:Circadian (~24 hour) clocks exist in almost all types of living organism and play a fundamental role in regulating daily physiological and behavioural processes. The transcription factor BMAL1 (ARNTL) is thought to be one of the principal drivers of the molecular clock in mammals since its deletion abolishes 24-hour activity patterning, an important physiological output of the clockwork. However, whether or not Bmal1-/- mice can nevertheless display molecular 24-hour rhythms is unknown. Here, we determined whether Bmal1 function is necessary for daily molecular oscillations in two tissues – skin fibroblasts and liver. Unexpectedly, both tissues exhibited robust 24-hour oscillations over 2-3 days in the absence of any exogenous synchronizers such as daily light or temperature cycles. This demonstrates a competent 24-hour molecular pacemaker in Bmal1 knockouts. Indeed, molecular oscillations were pervasive throughout the transcriptome, proteome and phosphoproteome of Bmal1-/- mice. In particular, several proteins exhibited rhythmic phosphorylation in both Bmal1-proficient and -deficient cells, highlighting an unanticipated role for post-translational regulators in 24-hour rhythms in the absence of any known clock mechanisms.

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