The Pentose Phosphate Pathway Regulates the Circadian Clock

Abstract

SummaryThe circadian clock is a ubiquitous timekeeping system that organizes the behavior and physiology of organisms over the day and night. Current models rely on transcriptional networks that coordinate circadian gene expression of thousands of transcripts. However, recent studies have uncovered phylogenetically conserved redox rhythms that can occur independently of transcriptional cycles. Here we identify the pentose phosphate pathway (PPP), a critical source of the redox cofactor NADPH, as an important regulator of redox and transcriptional oscillations. Our results show that genetic and pharmacological inhibition of the PPP prolongs the period of circadian rhythms in human cells, mouse tissues, and fruit flies. These metabolic manipulations also cause a remodeling of circadian gene expression programs that involves the circadian transcription factors BMAL1 and CLOCK, and the redox-sensitive transcription factor NRF2. Thus, the PPP regulates circadian rhythms via NADPH metabolism, suggesting a pivotal role for NADPH availability in circadian timekeeping.

Metabolic Plasticity Enables Circadian Adaptation to Acute Hypoxia in Zebrafish Cells

“…In this context, the reduced G6PDH activity of hypoxia treated cells (Fig. 4, B) indicates that the PPP might have an important regulatory function for circadian time keeping also in the present experimental setup, by adding to the oxidized environment through reduced production of reducing equivalents, hence confirming the role of glucose catabolism in the regulation of the TTFL amplitude reported previously [27, 50]. However, our results also implicate that a cellular timekeeping mechanism apart from the transcriptional clock is obviously quite robust against the stress of reduced oxygen tensions, in line with a recent review [50].…”

“…3, E and F), where we also found the G6PDH activity to be reduced (Fig. 4, B), an enzyme which was only recently reported to regulate the circadian clock [27]. The cytosolic redox state of cells depends on the generation of reactive oxygen species as well as on the production of reducing equivalents such as NADPH, NADH or Prx red .…”

“…Several other metabolites oscillate with a circadian rhythm as well, are controlled by the TTFL and feed back into the system, such as the cyclic biosynthesis of NAD+, which is mediated by the rate limiting and clock-controlled enzyme nicotinamide phosphoribosyl transferase (NAMPT) [21, 22], or the oscillating NAD+/NADH and NADP+/NADPH ratios, which enhance the binding of the CLOCK /BMAL1 complex to the DNA through higher levels of their reduced forms [23]. Models for the obvious crosstalk between metabolic oscillations and the TTFL were proposed by several authors [24-26] and only recently the pentose phosphate pathway (PPP), the main source of NADPH production as reducing equivalent was identified as a major regulator of the TTFL [27]. The influence of hypoxia on the TTFL has been investigated in several vertebrate studies [5, 7, 10, 14, 15] and the HIF-1α mediated dampening of specific core clock gene oscillation amplitudes, first described in zebrafish [10, 28] was specified recently also in mice [14, 15].…”

Reciprocal regulation of carbon monoxide metabolism and the circadian clock

“…However, additional potential mechanisms underlying the influence of heme oxygenases on circadian transcription and dynamics are not eliminated, because heme degradation also produces biliverdin and iron in addition to CO. Moreover, heme degradation consumes NADPH, whose intracellular concentration modulates circadian dynamics and expression of CLOCK-BMAL1-target genes 34 . However, relevant to the present findings, we consider it unlikely that an increase in NADPH levels-as predicted to occur after heme oxygenase depletion-would generate long circadian periods and upregulation of CLOCK-BMAL1 targets, because such effects have previously been associated with decreased levels of NADPH 34 .…”

Circadian Clocks and Metabolism: Implications for Microbiome and Aging

“…Over- and hyper-peroxidation rhythms of peroxiredoxins have been found in human red blood cells [25], which have no nucleus that are found to be driven by hemoglobin auto-oxidation rhythms and are associated with the degradation of hyperoxidized peroxiredoxins [26]. Inhibiting the pentose phosphate pathway, a critical source for NADPH, was found to influence circadian rhythms in cells across species [27], with a recent study showing an effect on the amplitude and phase of the clock [28] This work further supports a feedback from cellular energy metabolism to the transcriptional/translational circadian clock.…”