Regulation of lysosomal ion homeostasis by channels and transporters

Abstract

Lysosomes are the major organelles that carry out degradation functions. They integrate and digest materials compartmentalized by endocytosis, phagocytosis or autophagy. In addition to more than 60 hydrolases residing in the lysosomes, there are also ion channels and transporters that mediate the flux or transport of H+, Ca2+, Na+, K+, and Cl− across the lysosomal membranes. Defects in ionic exchange can lead to abnormal lysosome morphology, defective vesicle trafficking, impaired autophagy, and diseases such as neurodegeneration and lysosomal storage disorders. The latter are characterized by incomplete lysosomal digestion and accumulation of toxic materials inside enlarged intracellular vacuoles. In addition to degradation, recent studies have revealed the roles of lysosomes in metabolic pathways through kinases such as mechanistic target of rapamycin (mTOR) and transcriptional regulation through calcium signaling molecules such as transcription factor EB (TFEB) and calcineurin. Owing to the development of new approaches including genetically encoded fluorescence probes and whole endolysosomal patch clamp recording techniques, studies on lysosomal ion channels have made remarkable progress in recent years. In this review, we will focus on the current knowledge of lysosome-resident ion channels and transporters, discuss their roles in maintaining lysosomal function, and evaluate how their dysfunction can result in disease.

Lysosome enlargement during inhibition of the lipid kinase PIKfyve proceeds through lysosome coalescence

“…To enable their degradative capacity, lysosomes are equipped with a plethora of hydrolytic enzymes that digest proteins, lipids, nucleic acids, and carbohydrates. In addition, the vacuolar H + -pump ATPase generates a highly acidic lumen optimal for hydrolytic activity (Mindell, 2012;Schwake et al, 2013;Xiong and Zhu, 2016;Luzio et al, 2007). Nonetheless, the function of lysosomes is not limited to molecular degradation.…”

“…Nonetheless, the function of lysosomes is not limited to molecular degradation. Among other roles, lysosomes are an important storage organelle, they mediate antigen presentation, they undergo exocytosis to repair membrane damage, and are a genuine signalling platform that senses and informs the cell of its nutrient and stress conditions (Medina et al, 2015;Settembre and Ballabio, 2014;Sancak et al, 2010;Delamarre et al, 2005;Xiong and Zhu, 2016;Reddy et al, 2001;Settembre et al, 2012;Roczniak-Ferguson et al, 2012).…”

The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture

“…The lysosomal membrane is decorated with channels and transporters that regulate the lysosome’s ionic homeostasis and physiological functions 5,11,12 . Recently, a previously uncharacterized transmembrane protein 175 (TMEM175) was identified as the bona fide endo/lysosomal K + channel, whose function is important for setting the lysosomal membrane potential and maintaining pH stability 1 .…”

Two‐pore channels regulate Tat endolysosome escape and Tat‐mediated HIV‐1 LTR transactivation

“…A variety of endolysosome-resident calcium channels have been implicated in endolysosome calcium release including TRPML, TPC, TRPM2, P2X4, P-type, and L-type. [59][60][61] Using pharmacological approaches, we determined the extent to which blocking endolysosome calcium channels affected Tat-mediated LTR-transactivation. For these studies we blocked TPC with Ned-19, TRPML with ML-SI1, TRPM2 with flufenamic acid, P2X4 with 5-BDBD, P-type calcium channel with ω-agatoxin TK, and L-type calcium channels with verapamil.…”