Lysosomal Potassium Channels.

Lysosomes are acidic membrane-bound organelles that use hydrolytic enzymes to break down material through pathways such as endocytosis, phagocytosis, mitophagy, and autophagy. To function properly, intralysosomal environments are strictly controlled by a set of integral membrane proteins such as ion channels and transporters. Potassium ion (K+) channels are a large and diverse family of membrane proteins that control K+ flux across both the plasma membrane and intracellular membranes. In the plasma membrane, they are essential in both excitable and non-excitable cells for the control of membrane potential and cell signaling. However, our understanding of intracellular K+ channels is very limited. In this review, we summarize the recent development in studies of K+ channels in the lysosome. We focus on their characterization, potential roles in maintaining lysosomal membrane potential and lysosomal function, and pathological implications.

Multiple facets of TRPML1 in autophagy.

Autophagy is an evolutionarily conserved pathway that is required for cellular homeostasis, growth and survival. In a recent study, Scotto-Rosato et al. demonstrate that TRPML1-mediated calcium release promotes autophagosome biogenesis by activating the CaMKKß/VPS34 pathway, providing a new insight into the pathophysiological role of TRPML1 in human diseases.

The lysosomal TRPML1 channel regulates triple negative breast cancer development by promoting mTORC1 and purinergic signaling pathways.

The triple-negative breast cancer (TNBC) that comprises approximately 10%-20% of breast cancers is an aggressive subtype lacking effective therapeutics. Among various signaling pathways, mTORC1 and purinergic signals have emerged as potentially fruitful targets for clinical therapy of TNBC. Unfortunately, drugs targeting these signaling pathways do not successfully inhibit the progression of TNBC, partially due to the fact that these signaling pathways are essential for the function of all types of cells. In this study, we report that TRPML1 is specifically upregulated in TNBCs and that its genetic downregulation and pharmacological inhibition suppress the growth of TNBC. Mechanistically, we demonstrate that TRPML1 regulates TNBC development, at least partially, through controlling mTORC1 activity and the release of lysosomal ATP. Because TRPML1 is specifically activated by cellular stresses found in tumor microenvironments, antagonists of TRPML1 could represent anticancer drugs with enhanced specificity and potency. Our findings are expected to have a major impact on drug targeting of TNBCs.