Targeting TMEM175 in Lysosomal Physiology and Human Diseases

Abstract: The transmembrane protein TMEM175, a cation channel located on the lysosomal membrane, plays a crucial role in regulating lysosomal membrane potential and maintaining intralysosomal pH stability. It is involved in various physiological and pathological processes. This review summarizes recent advancements in understanding TMEM175’s role in lysosomal physiology, with a detailed discussion of its regulatory mechanisms and specific contributions to lysosomal function. Furthermore, it explores the potential links between TMEM175 and human diseases, particularly neurodegenerative disorders. The structure of TMEM175 is elaborated upon, highlighting how activators and inhibitors interact with different structural domains of TMEM175, revealing multiple potential active sites. The functional significance of these sites and their relationships with TMEM175’s activity are also discussed.