Physiology of endo-lysosomal ion channels in health and disease

Trafficking of intracellular membrane vesicles (endosomes and lysosomes) involve the formation, fusion, and fission of vesicles, as well as their tight interaction with filaments of the cytoskeleton and associated motor proteins. These processes are fundamental for life, occur in every cell of the body, and collectively regulate intracellular logistics, signaling, and intra- and intercellular communication. Defects in endosomal trafficking lead to various diseases such as metabolic disorders, infection, tumor development and growth, as well as neurodegenerative and cardiovascular diseases. The membranes of intracellular vesicles of the endo-lysosomal system contain a variety of ion channels, which control ion homeostasis (including pH control) of the vesicular lumen and the peri-vesicular microenvironment. Our group is particularly interested in two-pore channels (TPC1 and TPC2) and transient receptor potential mucolipin channels (TRPML1, 2, 3) that are localized in endo-lysosomal vesicles. These channels form a subgroup within the TRP (transient receptor) channel superfamily. In order to characterize the function of these channels in their specific intracellular vesicle system, we developed the endo-lysosomal patch clamp technique. Using this and other methods, we identified the role of TPC2 channels for hepatic and systemic lipoprotein and cholesterol homeostasis, for endo-lysosomal trafficking and cytosolic release of the Ebola virus, as well as for hair pigmentation. In addition, we discovered several other novel functions for TPCs, including their role in the acrosome reaction in sperm, in cancer cell migration, or in trafficking of bacterial toxins, e.g., cholera toxin. Currently, we are focusing on the role of TPCs, TRPML channels, and other ion channels in the brain and cardiovascular system.