The Pentose Phosphate Pathway Regulates the Circadian Clock

Area of Science:

• Circadian biology
• Metabolic regulation
• Cellular redox homeostasis

Background:

• Circadian clocks organize daily physiology via transcriptional networks.
• Emerging evidence points to redox rhythms influencing circadian timing independently of transcription.
• The pentose phosphate pathway (PPP) is a key source of the redox cofactor NADPH.

Purpose of the Study:

• To investigate the role of the pentose phosphate pathway (PPP) in regulating circadian rhythms.
• To determine if PPP activity influences both redox and transcriptional oscillations within the circadian system.

Main Methods:

• Genetic and pharmacological inhibition of the PPP in human cells, mouse tissues, and fruit flies.
• Analysis of circadian rhythm period length.
• Assessment of circadian gene expression programs involving BMAL1, CLOCK, and NRF2.

Main Results:

• Inhibition of the PPP significantly prolongs the period of circadian rhythms across different species.
• Metabolic manipulation of the PPP leads to remodeling of circadian gene expression.
• These changes involve key circadian transcription factors (BMAL1, CLOCK) and the redox-sensitive factor NRF2.

Conclusions:

• The pentose phosphate pathway (PPP) is a critical regulator of circadian rhythms.
• NADPH metabolism, influenced by the PPP, plays a pivotal role in circadian timekeeping.
• These findings link metabolic pathways directly to the molecular mechanisms of the circadian clock.