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

TL;DR

This study shows how a key metabolic enzyme in fruit flies connects energy levels to daily biological rhythms, offering new insight into how metabolism affects circadian clocks.

Contribution

The paper identifies a novel regulatory pathway involving Pyruvate kinase, TARANIS, and PDF that links glycolytic activity to circadian output.

Findings

Pyruvate kinase knock-down in adult Drosophila shortens circadian period and reduces PDF levels.

TARANIS mediates the effect of Pyruvate kinase on circadian rhythm and PDF expression.

Overexpression of TARANIS rescues the circadian and PDF defects caused by Pyruvate kinase knock-down.

Abstract

The circadian clock generates approximately 24-hour rhythms in behavior and physiology enabling organisms to anticipate daily environmental fluctuations. Circadian clock and glucose metabolism are tightly interconnected, and their disruption commonly co-occurs in aging and disease. However, how glucose hypometabolism specifically impacts circadian rhythm remains unclear. Here, we investigated this relationship by genetically downregulating key 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 circadian period in accordance with their mRNA reduction, inducing period lengthening and shortening, respectively. Notably, Pyk KD induced period shortening persisted in adult-specific KD (AKD), minimizing developmental confounds. Mechanistic analyses revealed that Pyk AKD reduced both PERIOD protein and Pigment-dispersing factor (PDF) levels. We identified TARANIS (TARA), a transcriptional coregulator recently shown to positively regulate PDF, as a crucial mediator of PYK’s effect. Pyk AKD lowered tara mRNA and protein levels, whereas tara overexpression in Pyk AKD rescued both the short-period phenotype and reduced PDF levels. Together, our findings establish a novel PYK-TARA-PDF regulatory axis linking glycolytic enzyme activity to circadian neuropeptide output, providing mechanistic insight into how metabolic dysfunction contributes to circadian disruption associated with aging and neurodegenerative diseases.

Figures