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.

Keywords: acid sphingomyelinase; cholesterol; intracellular trafficking; lysosomal disorders; lysosomes; mitochondria; sphingolipids.

Figure 1

ER and lysosomes in mitochondrial degradation. (A), Mitochondria and ER interaction through MAMs contributes to the uptake of calcium to mitochondria, which in physiological conditions do not cause mitochondrial dysfunction. However, in conditions of ER stress, enhanced flux of calcium from ER to mitochondria can cause oxidative stress, increased generation of reactive oxygen species (ROS) and mitochondrial depolarization. As a mechanism to ensure the elimination dysfunctional mitochondria, altered mitochondria is engulfed in sequential structures originating with the isolation membrane, which evolve to form autophagosomes. These structures encapsulating dysfunctional mitochondria are fused with lysosomes to form autolysosomes where mitocondria contained in the autolysosomes are degraded by acid hydrolases. (B), In LSD, such as NPA or NPC, lipid species accumulate in lysosomes, including sphingosine and cholesterol, which not only disrupt lysosomal calcium homeostasis through calcium channels (e.g., TRP) but also impair the fusion of lysosomes with autophagosomes leading to defective mitochondrial degradation. Moreover, defective engulfment of dysfunctional mitochondria may occur in earlier steps, which may favor the fragmentation of mitochondria. Of note, while the physical association between ER and mitochondria through MAMs are relatively well defined, the physical apposition between lysosomes and mitochondria is poorly understood and characterized. Dashed lines reflect defective steps in LSD leading to impaired autolysosome formation and defective digestion of dysfunctional mitochondria.

Figure 2

Similarities and differences between NPA and NPC. NPA disease due to ASMase deficiency is characterized by the primary accumulation of shingomyelin in lysosomes, which secondarily lead to the sequestration of cholesterol in these organelles. As ASMase triggers ER stress, the ablation of ASMase impairs ER stress signaling, and consequently the expression of StARD1. Thus, in NPA the bulk of cholesterol accumulation is restricted to lysosomes but not mitochondria, which allows the transport of GSH into the mitochondrial matrix via the 2-oxoglutarate carrier (OGC). In NPC, however, although primarily accumulates in lysosomes, mitochondrial cholesterol transporting polypeptides, such as MLN64 contribute to mitochondrial cholesterol loading. Moreover, besides MLN64, StARD1 is also induced in NPC cells by a poorly understood mechanism independent of ER stress, with the potential involvement of the downregulaton of acid ceramidase, which has been shown to repress StARD1 expression. The subsequent mitochondrial cholesterol accumulation then impairs the transport of GSH into mitochondria, resulting in mitochondrial GSH depletion and subsequent oxidative stress. These findings constitue the basis for the potential beneficial effects of mGSH replenishment by GSH ethyl ester in NPC.