Endolysosomal calcium regulation and disease

Abstract

Until recently, the mechanisms that regulate endolysosomal calcium homoeostasis were poorly understood. The discovery of the molecular target of NAADP (nicotinic acid-adenine dinucleotide phosphate) as the two-pore channels resident in the endolysosomal system has highlighted this compartment as an important calcium store. The recent findings that dysfunctional NAADP release leads to defective endocytic function which in turn results in secondary lipid accumulation in the lysosomal storage disease Niemann-Pick type C, is the first evidence of a direct connection between a human disease and defective lysosomal calcium release. In the present review, we provide a summary of the current knowledge on mechanisms of calcium homoeostasis within the endolysosomal system and how these mechanisms may be affected in human metabolic disorders.

Ganglioside accumulation in activated glia in the developing brain: comparison between WT and GalNAcT KO mice

“…Even when a primary defi ciency in a lysosomal glycohydrolase, activator protein, or saposin directly involved in the degradation of GM2 or GM3 ( 52 ) is not present, the accumulation of GM2/GM3 appears to occur, at least in part, in the endosomal/lysosomal system ( 26,29,30,34,53 ) and/or in lipid rafts ( 24,27,33 ). As well as for defi ciencies in catabolic proteins not directly involved in degradation of these gangliosides, defects in traffi cking of gangliosides from endosomes to the Golgi apparatus ( 53,54 ) or from late endosomes to lysosomes ( 55,56 ) also observed in some lysosomal storage diseases can produce similar accumulation. In chronic diseases, such ganglioside accumulation is typically detected in neurons ( 29,30,34,57 ) and, in some cases, in activated microglia ( 51 ).…”

Physiological roles of NAADP-mediated Ca2+ signaling

“…Ned19-induced effects on trafficking in wild type cells may indicate a physiological role for NAADP-mediated Ca 2+ release in endolysosomal physiology. Such defects are often observed in lysosomal storage disease phenotypes, and recently lysosomal Ca 2+ dysregulation has been presented as a causal factor in these diseases [75]. Particularly interesting recent findings are that cells from Niemann-Pick type C patients contain lysosomes with low Ca 2+ storage and defective NAADP-mediated Ca 2+ release [45].…”

“…Particularly interesting recent findings are that cells from Niemann-Pick type C patients contain lysosomes with low Ca 2+ storage and defective NAADP-mediated Ca 2+ release [45]. Conversely, in cells from patients with mucolipidosis IV which lack functional mucolipin 1 channels, NAADP-evoked Ca 2+ release is enhanced and associated with enlarged lysosomes [75].…”

Intracellular two-phase Ca2+ release and apoptosis controlled by TRP-ML1 channel activity in coronary arterial myocytes

“…9). In response to different physiological and pathological stimulations, lysosomal Ca 2ϩ can be mobilized or released to mediate molecular trafficking or recycling and to control vesicular fusion events associated with lysosomes (15,19,22). Recently, this lysosomal Ca 2ϩ release is found to be mediated by transient receptor potential-mucolipin 1 (TRP-ML1) channel, a…”

“…signaling lysosomes; transient receptor potential channel; Ca 2ϩ mobilization; programmed cell death LYSOSOME-MEDIATED SIGNALING is a novel mechanism that regulates intracellular Ca 2ϩ levels in a variety of mammalian cells (15,18). It has been reported that lysosomes contain high levels of Ca 2ϩ , which serve as an important intracellular Ca 2ϩ store as does the sarcoplasmic reticulum (SR; Ref.…”