Nuclear functional role of metabolic enzymes and related metabolites: Focus on gene expression regulation

Background: Many biological processes from physiological development to different pathological conditions are closely linked to dynamic energetic metabolism and its dysregulations. Mounting evidence shows that metabolic rewiring allows cells to adapt to stress conditions, changes in extracellular cues, and nutritional fluctuations in a timely and precise manner by modulating gene expression. Recent studies reveal non-strictly metabolic functions of metabolic enzymes and related metabolites often confined to the nucleus. Indeed, beyond the diffusion of metabolites through nuclear pores, several metabolic enzymes translocate to the nucleus during cellular differentiation, macrophage activation, tumorigenesis, and so on. Scope of review: This review aims to outline recent advances in the nuclear functions of metabolic enzymes, focusing on gene expression regulation through transcription factors and epigenetic mechanisms. Major conclusions: The nuclear localization of metabolic enzymes and metabolites underlines the dual role of metabolism as both a driver and a controller of cellular processes by linking energy metabolism directly to gene expression and cellular reprogramming. The main involvement of respiratory enzymes in nuclear functions suggests a ready interplay between energy status and transcriptional regulation. We trust that these insights will contribute to a more extensive knowledge of the cellular and nuclear landscape and could inspire future investigations on metabolic-mediated gene regulation mechanisms with the aim of developing more effective therapies against diseases.