Lysosomes, the cell's degradation center, are filled with acidic hydrolases. Lysosomes generate nutrient-sensitive signals to regulate the import of H + , hydrolases, and endocytic and autophagic cargos, and the export of the degradation products (catabolites). In response to environmental and cellular signals, lysosomes change their positioning, number, morphology, size, composition, and activity within minutes to hours to meet the changing cellular needs. Ion channels in the lysosome are essential transducers that mediate signal-initiated Ca 2+ /Fe 2+ /Zn 2+ release and H + /Na + /K +dependent changes of membrane potential across the perimeter membrane. Dysregulation of lysosomal ion flux impairs lysosome movement, membrane trafficking, nutrient-sensing, membrane repair, organelle membrane contact, and lysosome biogenesis and adaptation. Hence, activation and inhibition of lysosomal channels by synthetic modulators may tune lysosome function to maintain cellular health and promote cellular clearance in lysosome storage disorders.

Ion-dependent channels and transporters have been identified in lysosomes, including the V-ATPase H+ pump and transient receptor potential mucolipin channels (TRPMLs), the principle Ca2+ release channels in the lysosome, but much less is understood about the roles of Na+ and K+ in lysosomal physiology. Wang et al. describe a voltage-sensitive, Ca2+-activated K+ current in the lysosome (LysoKVCa) and show that LysoKVCa regulates lysosomal membrane potential and refilling of lysosomal Ca2+ stores.

Cells utilize calcium ions (Ca) to signal almost all aspects of cellular life, ranging from cell proliferation to cell death, in a spatially and temporally regulated manner. A key aspect of this regulation is the compartmentalization of Ca in various cytoplasmic organelles that act as intracellular Ca stores. Whereas Ca release from the large-volume Ca stores, such as the endoplasmic reticulum (ER) and Golgi apparatus, are preferred for signal transduction, Ca release from the small-volume individual vesicular stores that are dispersed throughout the cell, such as lysosomes, may be more useful in local regulation, such as membrane fusion and individualized vesicular movements. Conceivably, these two types of Ca stores may be established, maintained or refilled via distinct mechanisms. ER stores are refilled through sustained Ca influx at ER-plasma membrane (PM) membrane contact sites (MCSs). In this review, we discuss the release and refilling mechanisms of intracellular small vesicular Ca stores, with a special focus on lysosomes. Recent imaging studies of Ca release and organelle MCSs suggest that Ca exchange may occur between two types of stores, such that the small stores acquire Ca from the large stores via ER-vesicle MCSs. Hence vesicular stores like lysosomes may be viewed as secondary Ca stores in the cell.

Axon pathology has been widely reported in Alzheimer’s disease (AD) patients and AD mouse models. Herein we report that increased miR-342–5p down-regulates the expression of ankyrin G (AnkG), a protein known to play a critical role in establishing selective filtering machinery at the axon initial segment (AIS). Diminished AnkG expression leads to defective AIS filtering in cultured hippocampal neurons from AD mouse models, as monitored by selective exclusion of large macromolecules from the axons. Furthermore, AnkG-deficiency impairs AIS localization of Nav 1.6 channels and confines NR2B to the somatodendritic compartments. The expression of exogenous AnkG improved the cognitive performance of 12-mo-old APP/PS1 mice; thus, our data suggest that AnkG and impairment of AIS filtering may play important roles in AD pathology.