Protein aggregation and biomolecular condensation in hypoxic environments (Review)

Abstract

Due to molecular forces, biomacromolecules assemble into liquid condensates or solid aggregates, and their corresponding formation and dissolution processes are controlled. Protein homeostasis is disrupted by increasing age or environmental stress, leading to irreversible protein aggregation. Hypoxic pressure is an important factor in this process, and uncontrolled protein aggregation has been widely observed in hypoxia-related conditions such as neurodegenerative disease, cardiovascular disease, hypoxic brain injury and cancer. Biomolecular condensates are also high-order complexes assembled from macromolecules. Although they exist in different phase from protein aggregates, they are in dynamic balance under certain conditions, and their activation or assembly are considered as important regulatory processes in cell survival with hypoxic pressure. Therefore, a better understanding of the relationship between hypoxic stress, protein aggregation and biomolecular condensation will bring marked benefits in the clinical treatment of various diseases. The aim of the present review was to summarize the underlying mechanisms of aggregate assembly and dissolution induced by hypoxic conditions, and address recent breakthroughs in understanding the role of aggregates in hypoxic-related diseases, given the hypotheses that hypoxia induces macromolecular assemblage changes from a liquid to a solid phase, and that adenosine triphosphate depletion and ATP-driven inactivation of multiple protein chaperones play important roles among the process. Moreover, it is anticipated that an improved understanding of the adaptation in hypoxic environments could extend the overall survival of patients and provide new strategies for hypoxic-related diseases.