ADAPTATION OF THE CIRCADIAN CLOCK TO LOW NUTRIENT SUPPLY IN NEUROSPORA CRASSA
Sárkány Orsolya
Molecular Medicine Division
Dr. Várnai Péter
Semmelweis Egyetem Elméleti Orvostudományi Központ Hári Pál Előadóterem
2026-02-02 14:00:00
Cellular and Molecular Physiology
Dr. Hunyady László
Dr. Káldi Krisztina
Kozma-Bognár László
Sipeki Szabolcs
Dr. Wiener Zoltán
Dr. Liliom Károly
Dr. Apáti ágota
The circadian clock enables organisms to anticipate and adapt to daily environmental cycles. A key property of the clock is its robustness against metabolic fluctuations, allowing it to maintain a stable period across varying nutrient levels - known as metabolic compensation. This dissertation investigates the molecular mechanisms underlying nutrient-dependent modulation of the circadian clock, using Neurospora crassa as a model organism, and explores the conservation of these mechanisms in mammalian cells.
In Neurospora, we found that the circadian clock remains functional under glucose starvation, despite a marked decrease in cytoplasmic WCC levels and hyperphosphorylation of FRQ. Nuclear WCC levels were preserved, allowing stable frq expression and circadian oscillation. However, light-induced transcriptional activation was attenuated under starvation, suggesting weakened photoreceptor function. Our results also showed that the frq mRNA decay rate did not differ between nutrient conditions, indicating that frq RNA stability is unaffected by glucose availability. We further identified key signalling components that mediate these compensatory responses. Using mutant strains, we showed that PKA activity modulates starvation-induced changes in clock components. GSK was necessary for FRQ hyperphosphorylation, and partial disruption of FRQ-CK-1a interaction affected WCC levels.
Furthermore, we identified RasGEF, a guanine nucleotide exchange factor, as an essential regulator of clock robustness under nutrient limitation. Loss of rasgef impairs metabolic and temperature compensation, disrupts rhythmic gene expression, and alters the timely pattern of conidiation. Importantly, RasGEF signals through RAS2P and affects the cAMP/PKA pathway, reinforcing the integration of nutrient sensing with circadian regulation.
Finally, we extended our findings to mammalian cells using U2OS cell lines expressing Bmal1-luciferase. Luminescence rhythms remained stable across a wide glucose concentration range (0.5-25 mM), and pharmacological inhibition of SOS1 or ERK signalling revealed their importance for circadian robustness under low glucose conditions. These results suggest that RasGEF/SOS1-mediated pathways are conserved regulators of nutrient compensation in eukaryotic clocks.
Together, these results identify molecular pathways that maintain clock function during nutrient limitation and provide evidence for their evolutionary conservation.
