Drosophila Pyruvate Kinase Links Metabolic State with Circadian Output via TARANIS and PDF

Abstract

The circadian clock generates [~]24-hour rhythms that anticipate daily environmental changes. Circadian clock and glucose metabolism are tightly interconnected, and both are disrupted in aging and disease. To examine how glucose hypometabolism impacts circadian rhythm, we downregulated glycolytic enzymes - Hexokinase-C (Hex-C), Phosphofructokinase (Pfk), and Pyruvate kinase (Pyk) - in Drosophila clock cells. Only Hex-C and Pyk knock-down (KD) altered period, lengthening and shortening rhythms, respectively. Notably, Pyk KD induced period shortening persisted in adult-specific KD (AKD), indicating a role independent of developmental effects. Pyk AKD reduced both PERIOD and Pigment-dispersing factor (PDF) protein levels, with PDF loss driving the short-period phenotype. Mechanistically, the transcriptional co-regulator TARANIS (TARA) was required: Pyk AKD lowered tara expression, while tara overexpression rescued PDF and circadian period. Our findings identify a novel PYK-TARA-PDF regulatory axis linking glycolytic activity to circadian neuropeptide output, providing mechanistic insight into how metabolic dysfunction contributes to circadian disruption in aging and neurodegenerative diseases.