Is the succinate/SUCNR1 axis a fulcrum of cellular clocks?

ongoing

Our circadian clock controls a wide range of physiological processes to respond to external demands through a fine-tuning coordination between the hypothalamic central clock and the peripheral clocks. Understanding the bidirectional communication and the reliance on external cues that specifically affect these clocks is of paramount importance. Yet, both circadian clocks can function even in the absence of these external signals, highlighting their endogenous nature. This underscores the existence of endogenous signals such as metabolites and other biomolecules that can modulate the circadian clocks. Surprisingly, this aspect remains largely unexplored in current research. Succinate is both an energetic metabolic product of mitochondrial activity and a byproduct of the microbiota, with critical physiological roles in cellular function at various levels. Furthermore, in the last years, succinate is emerging as a biomarker for early detection of metabolic dysfunction and cardiovascular risk. As a basis for the current proposal, we have recently reported, via an untargeted approach, that succinate regulates core-clock genes in adipocytes via its cognate receptor, SUCNR1. Thus, building upon our previous studies, we propose that succinate may serve as a pivotal endogenous signal capable of modulating the circadian clocks. Within the framework of this project, we present for the first time the concept of succinate as a link between metabolism and circadian clocks. To accomplish our goals, we will employ the complementary expertise between Dr Fernández-Veledo (supervisor and renowned expert in the succinate/SUCNR1 axis) and Dr Ribas (candidate and expert in chronobiology). By merging these two fields, we aim to integrate the notion of temporality into the succinate/SUCNR1 axis, and advance our understanding of the intricate relationship between metabolism and circadian rhythms.