Molecular mechanisms of endolysosomal Ca²⁺ signalling in health and disease

Endosomes, lysosomes and lysosome-related organelles are emerging as important Ca²⁺ storage cellular compartments with a central role in intracellular Ca²⁺ signalling. Endocytosis at the plasma membrane forms endosomal vesicles which mature to late endosomes and culminate in lysosomal biogenesis. During this process, acquisition of different ion channels and transporters progressively changes the endolysosomal luminal ionic environment (e.g. pH and Ca²⁺) to regulate enzyme activities, membrane fusion/fission and organellar ion fluxes, and defects in these can result in disease. In the present review we focus on the physiology of the inter-related transport mechanisms of Ca²⁺ and H⁺ across endolysosomal membranes. In particular, we discuss the role of the Ca²⁺-mobilizing messenger NAADP (nicotinic acid adenine dinucleotide phosphate) as a major regulator of Ca²⁺ release from endolysosomes, and the recent discovery of an endolysosomal channel family, the TPCs (two-pore channels), as its principal intracellular targets. Recent molecular studies of endolysosomal Ca²⁺ physiology and its regulation by NAADP-gated TPCs are providing exciting new insights into the mechanisms of Ca²⁺-signal initiation that control a wide range of cellular processes and play a role in disease. These developments underscore a new central role for the endolysosomal system in cellular Ca²⁺ regulation and signalling.