Lysosomal Ion Channels: What Are They Good For and Are They Druggable Targets?

Abstract

Lysosomes play fundamental roles in material digestion, cellular clearance, recycling, exocytosis, wound repair, Ca2+ signaling, nutrient signaling, and gene expression regulation. The organelle also serves as a hub for important signaling networks involving the mTOR and AKT kinases. Electrophysiological recording and molecular and structural studies in the past decade have uncovered several unique lysosomal ion channels and transporters, including TPCs, TMEM175, TRPMLs, CLN7, and CLC-7. They underlie the organelle's permeability to major ions, including K+, Na+, H+, Ca2+, and Cl−. The channels are regulated by numerous cellular factors, ranging from H+ in the lumen and voltage across the lysosomal membrane to ATP in the cytosol to growth factors outside the cell. Genetic variations in the channel/transporter genes are associated with diseases that include lysosomal storage diseases and neurodegenerative diseases. Recent studies with human genetics and channel activators suggest that lysosomal channels may be attractive targets for the development of therapeutics for the prevention of and intervention in human diseases. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 63 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The Emerging Role of Autophagy as a Target of Environmental Pollutants: An Update on Mechanisms

“…It has also been found that lysosomal membranes and ATP-dependent proton pumps keep the lumen acidic for enzyme activity [ 47 ]. However, lumen pH or lysosomal membrane permeability variations cause lysosome dysfunction, disrupting the autophagosome–lysosome fusion [ 48 ]. Changes in membrane permeability can produce acidification and necrosis.…”

Optical recordings of organellar membrane potentials and the components of membrane conductance in lysosomes

“…In eukaryotic cells, organelles orchestrate cellular homeostasis by integrating signalling and controlling the metabolic landscape (Julian & Stanford, 2020; Kat et al., 2022; Lawrence & Zoncu, 2019; Pfannschmidt et al., 2020; Savini et al., 2019; van Oosten‐Hawle & Morimoto, 2014; Yu & Yu, 2021; Zheng & Xiang, 2022). Ion channels, transporters and pumps support the selective passage of ions through the organellar membrane, providing a transmembrane drop in voltage that is used as a driving force for the transport of metabolites and byproducts of metabolic activity (Hille, 2001; Ishida et al., 2013; Jentsch et al., 2005; Palmieri, 2013; Riederer et al., 2023). Thus, the natural transit of chemical species through ion‐coupled facilitative transporters and/or the activation or inhibition of resident ion channels by signalling intermediates impacts the organellar membrane potential (Ψ org ) directly (Clapham & Ehrlich, 1996; Halestrap, 2013; Hayashi et al., 2006; Jain & Zoncu, 2022; Xu et al., 2015).…”

“…These have been implicated in various human pathological conditions associated with lysosomal storage diseases, such as neurodegenerative diseases, metabolic disorders and cancer (Ellison et al., 2023; Pfrieger, 2023; Shin et al., 2019; Toledano‐Zaragoza & Ledesma, 2020). Lysosomal storage diseases can arise from mutations in lysosomal enzymes, but naturally occurring variations in the expression and/or function of lysosomal ion channels and transporters can also lead to lysosomal storage diseases (Bissa et al., 2016; Cao et al., 2015; Feng et al., 2018; Huizing & Gahl, 2020; Kendall & Holian, 2021; Onyenwoke et al., 2015; Riederer et al., 2023; Shen et al., 2012; Zhang et al., 2018). Therefore, studying the electrophysiological properties of the lysosome and biophysics of ion transport systems in their native environment becomes crucial, because the establishment, maintenance and controlled changes in the membrane voltage are likely to play a fundamental physiological role.…”

“…Numerous ion transport systems are responsible for maintaining the electrical properties of the lysosomal membrane, and a failure to do so can have pathological consequences (Feng et al., 2018; Kendall & Holian, 2021; Riederer et al., 2023). At least 10 distinct ion transport systems have been identified in the lysosome, and these are responsible for the permeability to H + , K + , Na + , Ca 2+ and Cl − (Chen et al., 2017; Li et al., 2019; Riederer et al., 2023).…”

“…Numerous ion transport systems are responsible for maintaining the electrical properties of the lysosomal membrane, and a failure to do so can have pathological consequences (Feng et al., 2018; Kendall & Holian, 2021; Riederer et al., 2023). At least 10 distinct ion transport systems have been identified in the lysosome, and these are responsible for the permeability to H + , K + , Na + , Ca 2+ and Cl − (Chen et al., 2017; Li et al., 2019; Riederer et al., 2023). To gain a better understanding of whether the interplay between different ion transport systems affects the electrical properties of the lysosome, we developed a mathematical model that takes into account the major ion fluxes reported for the lysosomal membrane (for details, see Annex 1).…”