Protein phase separation disorder as a potentially pervasive pathogenic mechanism of male infertility

Male infertility is a complicated pathological state with high genetic susceptibility. Genetic defects and gene mutations may affect the structure and function of key molecules associated with fertility, and then clinically manifest as azoospermia, teratospermia, oligozoospermia, or asthenozoospermia. Most of the current research mainly focuses on the infertility phenotype and downstream pathways and clarifies the relevant mechanism by using molecular biology methods to construct knockout or overexpression models combined with omics and experimental verification, but how the mutation itself affects biomacromolecular functions remains poorly understood. As a special state of intracellular aggregation of biological macromolecules, phase separation (PS) is closely related to many important basic life activities. It has been reported to participate in the occurrence and development of various diseases, including neurodegenerative diseases, cardiovascular diseases and tumors, but only a few reports addressed the potential impact of protein PS on fertility. Given the physiological characteristics of PS, we hypothesize that abnormal PS may be a common pathological regulatory mechanism of male infertility, especially spermatogenesis and maturation disorders. PS can affect spermatogenesis and maturation by interfering with the phase transition of key molecules or molecular clusters, leading to gamete loss or dysfunction. Targeted modulation of PS may be a potentially powerful means to improve male fertility.