A pH-Centric Model of Nucleolar Activity and Regulation

The nucleolus is essential for the efficient and accurate production of ribosomal subunits, which are crucial for assembling ribosomes—the cellular machinery responsible for protein synthesis. Emerging insights into its liquid-like nature have shed new light on the role of its unique biophysical properties in the activity and regulation of this organelle. In this perspective, we examine recent insights into nucleolar biophysical homeostasis, with a focus on its regulation as an acidic biomolecular condensate. We review current evidence on how nucleolar composition and biochemical activities could generate and maintain a proton gradient. Additionally, we propose an integrative model explaining how nucleolar acidity contributes to homeostasis at a molecular level, providing a unified framework for its role in health and disease.