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.
Highlights
Mammalian models of the circadian clock center on transcription-translation feedback loop mechanisms, involving the core transcription factors BMAL1 and CLOCK (Bass, 2012)
Inhibition of the phosphate pathway (PPP) Alters Circadian Redox and Transcriptional Oscillations In red blood cells, peroxiredoxin oxidation rhythms resonate with NADPH oscillations (O’Neill and Reddy, 2011)
We measured NADPH accumulation in human osteosarcoma (U2OS) cells, an established and robust cellular clock model (Liu et al, 2008), and found similar redox oscillations to those seen in red blood cells previously (O’Neill and Reddy, 2011) (Figure 1B)
Summary
Mammalian models of the circadian clock center on transcription-translation feedback loop mechanisms, involving the core transcription factors BMAL1 and CLOCK (Bass, 2012). Recent evidence has uncovered the existence of transcription-independent mechanisms of circadian timekeeping (Cho et al, 2014; Nakajima et al, 2005; O’Neill and Reddy, 2011; O’Neill et al, 2011) These likely preceded the existence of transcriptional oscillations during evolution, as highlighted by rhythms in the oxidation and reduction of peroxiredoxin proteins in a range of phylogenetically disparate organisms ranging from bacteria to humans (Edgar et al, 2012). Glycolysis and the pentose phosphate pathway (PPP) oxidize glucose to produce NADH and NADPH, respectively (Figure 1A) These pathways are common to most aerobic organisms and produce an important fraction of the cellular pool of NAD(P)H (Fan et al, 2014). Since the peroxiredoxin oxidation cycle is directly influenced by the availability of NADPH (Wood et al, 2003), we hypothesized that these cellular reduction pathways might regulate redox and transcriptional oscillations in nucleated cells
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