Lysosomal exocytosis and lipid storage disorders

Abstract

respective smaller building-block molecules: amino acids, monosaccharides, free fatty acids, or nucleotides ( 1-4 ). Hence, since their discovery by Christian De Duve in 1955, lysosomes have been viewed as the cell's degradation center ( 3,5 ). Lysosomes, several hundreds of them in each mammalian cell, are heterogeneous in size (100-1,000 nm) and morphology, and collectively constitute ‫ف‬ 5% of the cell volume ( 6 ). Lysosomes are filled with more than 50 different types of hydrolases: sulphatases, phosphatases, lipases, proteases, carbohydrases, and glycosidases, which effectively catabolize proteins and complex lipids into their building-block molecules ( 1, 4 ). The functions of most lysosomal hydrolytic enzymes require an acidic lumen, which is established and maintained by the vacuolarATPase (V-ATPase)... proton pumps located on the perimeter limited membrane ( 6 ). To protect the perimeter membrane and its resident membrane proteins from degradation, the inner leafl et of the lysosomal membrane is coated with a polysaccharide layer called the glycocalyx ( 7 ).The biomaterials destined for degradation are delivered to lysosomes through endocytic/phagocytic and autophagic pathways ( Fig. 1 ). Endocytosis or phagocytosis of extracellular particles or plasma membrane proteins begins with the invagination of the plasma membrane to form endocytic vesicles, which then undergo a series of maturation processes to fi rst become early endosomes, and then late endosomes [excellently reviewed in ( 5 )] ( Fig. 1 ). In the late endosomes, the destined-to-be-degraded cargo is sorted into the intraluminal vesicles via the endosomal sorting complexes required for transport system ( 5 ). Intraluminal Abstract Lysosomes are acidic compartments in mammalian cells that are primarily responsible for the breakdown of endocytic and autophagic substrates such as membranes, proteins, and lipids into their basic building blocks. Lysosomal storage diseases (LSDs) are a group of metabolic disorders caused by genetic mutations in lysosomal hydrolases required for catabolic degradation, mutations in lysosomal membrane proteins important for catabolite export or membrane traffi cking, or mutations in nonlysosomal proteins indirectly affecting these lysosomal functions. A hallmark feature of LSDs is the primary and secondary excessive accumulation of undigested lipids in the lysosome, which causes lysosomal dysfunction and cell death, and subsequently pathological symptoms in various tissues and organs. There are more than 60 types of LSDs, but an effective therapeutic strategy is still lacking for most of them. Several recent in vitro and in vivo studies suggest that induction of lysosomal exocytosis could effectively reduce the accumulation of the storage materials. Meanwhile, the molecular machinery and regulatory mechanisms for lysosomal exocytosis are beginning to be revealed. In this paper, we fi rst discuss these recent developments with the focus on the functional interactions between lipid storage and lysosomal exocytosis. We th...

Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation

“…Given the timeframe for autophagosome-lysosome fusion (0.5-4 h after starvation) (8), ML1 upregulation may promote Ca 2+ -dependent fusion of autophagosomes and lysosomes (Fig. 7C) for the autophagy process (15,44). ML1 channels may also be directly sensitized via a posttranslational mechanism, thereby increasing lysosomal activity and proteolytic function.…”

“…response to trafficking cues, such as changes in levels of PI(3,5)P 2 , a lysosome-localized phosphoinositide (7,15,(18)(19)(20)(21). ML1-mediated lysosomal Ca 2+ release may regulate many aspects of lysosomal trafficking, including lysosome to trans-Golgi-network (TGN) retrograde trafficking, autophagosome-lysosome fusion, lysosome reformation, and lysosomal exocytosis (15,19,22,23).…”

“…ML1-mediated lysosomal Ca 2+ release may regulate many aspects of lysosomal trafficking, including lysosome to trans-Golgi-network (TGN) retrograde trafficking, autophagosome-lysosome fusion, lysosome reformation, and lysosomal exocytosis (15,19,22,23). Moreover, it has been demonstrated that nutrient starvation affects phosphoinositide dynamics and Ca 2+ signaling (16,18,24).…”

“…Lysosomal ionic conductance regulates all aspects of lysosome function, including lysosomal degradation, catabolite export, and membrane trafficking (15). Hence, regulation of lysosomal conductance by environmental cues may serve as a primary mechanism for lysosome adaptation (16,17).…”

Reversal of Pathologic Lipid Accumulation in NPC1-Deficient Neurons by Drug-Promoted Release of LAMP1-Coated Lamellar Inclusions

“…Examples are the age-dependent formation of lipofuscin (Nowotny et al, 2014) and the pathologic aggregation of macromolecules in Alzheimer's disease (Lim and Yue, 2015) and lysosomal storage disorders (Samie and Xu, 2014;Parenti et al, 2015). In most cases, it is unknown where the macromolecular complexes form, how they damage neurons, and whether they can be dissolved.…”