Abstract:
Cellular homeostasis requires the continuous and dynamic coordination of biochemical processes across organelles and intracellular compartments in response to both extracellular cues and intrinsic metabolic demands. The maintenance of protein homeostasis, the proper function of the secretory pathway, and organelle integrity all depend on highly integrated sensing and signaling mechanisms that activate appropriate adaptive responses. In this context, real-time preservation of endoplasmic reticulum (ER)/secretory pathway homeostasis is fundamental. It safeguards ER structural integrity, folding capacity, lipid composition, Ca²⁺ storage, and degradative efficiency, thereby ensuring that protein synthesis and secretory trafficking proceed without triggering proteotoxic or metabolic stress. Key cellular metabolites -reflecting the immediate activity of metabolic enzymes as well as the functional state of intracellular organelles- have emerged as potent signaling regulators. These metabolites influence enzymatic kinetics and modulate transcriptional, translational, and post-translational processes. Among these, the citrate/acetyl-CoA axis represents a central metabolic node with broad regulatory impact. Fluctuations in acetyl-CoA availability across subcellular compartments provide substrate-level control over diverse proteins and pathways. Indeed, numerous biological processes are directly modulated by Nε-lysine acetylation, whose extent is dictated by the intracellular availability and compartmentalization of acetyl-CoA. ER homeostasis is increasingly recognized as a metabolite-sensitive system in which changes in nutrient flux are translated into structural remodeling and proteostatic adaptation.