Effects of pH alterations on stress- and aging-induced protein phase separation

Abstract Upon stress challenges, proteins/RNAs undergo liquid–liquid phase separation (LLPS) to fine-tune cell physiology and metabolism to help cells adapt to adverse environments. The formation of LLPS has been recently linked with intracellular pH, and maintaining proper intracellular pH homeostasis is known to be essential for the survival of organisms. However, organisms are constantly exposed to diverse stresses, which are accompanied by alterations in the intracellular pH. Aging processes and human diseases are also intimately linked with intracellular pH alterations. In this review, we summarize stress-, aging-, and cancer-associated pH changes together with the mechanisms by which cells regulate cytosolic pH homeostasis. How critical cell components undergo LLPS in response to pH alterations is also discussed, along with the functional roles of intracellular pH fluctuation in the regulation of LLPS. Further studies investigating the interplay of pH with other stressors in LLPS regulation and identifying protein responses to different pH levels will provide an in-depth understanding of the mechanisms underlying pH-driven LLPS in cell adaptation. Moreover, deciphering aging and disease-associated pH changes that influence LLPS condensate formation could lead to a deeper understanding of the functional roles of biomolecular condensates in aging and aging-related diseases.