Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease

Abstract

Lysosomal storage disorders (LSD) are characterized by the accumulation of diverse lipid species in lysosomes. Niemann-Pick type A/B (NPA/B) and type C diseases Niemann-Pick type C (NPC) are progressive LSD caused by loss of function of distinct lysosomal-residing proteins, acid sphingomyelinase and NPC1, respectively. While the primary cause of these diseases differs, both share common biochemical features, including the accumulation of sphingolipids and cholesterol, predominantly in endolysosomes. Besides these alterations in lysosomal homeostasis and function due to accumulation of specific lipid species, the lysosomal functional defects can have far-reaching consequences, disrupting intracellular trafficking of sterols, lipids and calcium through membrane contact sites (MCS) of apposed compartments. Although MCS between endoplasmic reticulum and mitochondria have been well studied and characterized in different contexts, emerging evidence indicates that lysosomes also exhibit close proximity with mitochondria, which translates in their mutual functional regulation. Indeed, as best illustrated in NPC disease, alterations in the lysosomal-mitochondrial liaisons underlie the secondary accumulation of specific lipids, such as cholesterol in mitochondria, resulting in mitochondrial dysfunction and defective antioxidant defense, which contribute to disease progression. Thus, a better understanding of the lysosomal and mitochondrial interactions and trafficking may identify novel targets for the treatment of Niemann-Pick disease.

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

“…Beyond their important metabolic role, lipid droplets can also prevent lipo-toxicity (Greenberg, Coleman et al, 2011, Krahmer, Farese et al, 2013 or protect cells from high reactive oxygen species (ROS) (Bailey, Koster et al, 2015, Liu, MacKenzie et al, 2017, Liu, Zhang et al, 2015, ER stress or mitochondrial damage (Nguyen, Louie et al, 2017, Olzmann & Carvalho, 2019, Torres, Balboa et al, 2017. Thus, disturbances in lipid droplet formation in Npc1 -/microglia may contribute to increased cellular stress and neurotoxicity (Dionisio-Santos, Olschowka et al, 2019).…”

Mitochondrial biogenesis is transcriptionally repressed in lysosomal lipid storage diseases

“…2014). However, while mitochondria in NPC also present increased levels of cholesterol, this does not happen in ASM deficiency (Torres et al, 2017).…”

“…Since excessive mitochondrial cholesterol can impair mitochondrial function (Torres et al, 2017), we tested if ASM deficiency would also have a repressive effect on mitochondrial biogenesis. Similar to the NPC findings, we observed a decrease in the expression of mitochondria-associated genes in the ASM KO liver compared to the WT littermates ( Figure 2C) as well as in two different patient fibroblasts of ASM deficiency ( Figure 2D).…”

“…Furthermore, the mitochondrial impairments are likely unrelated to the levels of cholesterol in mitochondria (known to be high in NPC but normal in ASM; Torres et al, 2017), and seem rather a consequence of the lysosomal saturation in NPC and ASM deficiency.…”

“…Furthermore, lysosomes are essential for the process of macroautophagy, and thus for the selective autophagy of mitochondria, the main mechanism to degrade dysfunctional mitochondria (Pickles et al, 2018). Mitochondrial perturbations have been widely reported in several lysosomal storage diseases (Platt et al, 2012;Plotegher and Duchen, 2017), including neuronal ceroid lipofuscinosis, Gaucher and Niemann-Pick diseases (Jolly et al, 2002;Lim et al, 2015;Osellame et al, 2013;Torres et al, 2017;Wos et al, 2016). Nevertheless, it remains unclear why mitochondrial dysfunction is so prevalent in lysosomal storage diseases.…”